Adopting a strike-while-the-iron-is-hot mentality, the U.S. government’s Advanced Research Projects Agency for Health (ARPA-H) recently signaled support for personalized, RNA-based medicines and—equally as crucially—the cutting-edge manufacturing solutions that would be needed to deliver those bespoke treatments at scale.
Under the auspices of the agency’s Genetic Medicines and Individualized Manufacturing for Everyone (GIVE) program, ARPA-H is offering up to $125 million to five teams who will work to devise systems to automate the production and quality control of on-demand, patient-tailored RNA-based medicines.
The objective, according to an agency communique in early September, is to liberate next-generation therapeutics from major biomanufacturing hubs and to eventually enable their production closer to the patients they serve.
The move comes amid an outpouring of policy efforts and industry investments meant to nurture the United States’ biomanufacturing base. But rather than another instance of on-shoring enthusiasm, ARPA-H’s personalized RNA drug production network project should be viewed as more akin to a “first-shoring program,” said John Schiel, Ph.D., program manager for GIVE at ARPA-H.
“We talk a lot about on-shoring,” he explained in an interview with Fierce, “but we’re essentially building the capability before we need it, so that the U.S. does have the ability to bring these new products to market and be the first to bring these new products to market.”
Meanwhile, the broader question of why personalized medicine—and why now—is “kind of tied directly into RNA,” Schiel pointed out.
“For the first time, we actually have a modality that can do personalized neoantigen therapies, can do gene editing, can do … on-demand CAR RNA,” he said. “There are several different types of advanced therapy modalities that can be performed by RNA, and it just so happens that the manufacturing process is more synthetic, as opposed to needing cell-based systems.”
Beyond production, ARPA-H is pitching in on personalized RNA-based drug development efforts too, announcing an up to $160 million commitment in July under its closely related THRIVE program to support the creation of platforms for personalized therapies, with a particular focus on the treatment of rare pediatric diseases.
Both that initiative and the production-minded contribution through GIVE are in no small part influenced by the story of Baby KJ, who last year made history as the first patient treated with an in vivo CRISPR gene editing therapy designed just for him.
With that growing therapeutic promise in mind, there’s also been “this confluence of events in the technology” on the manufacturing-side of the RNA equation, Schiel explained, noting that it’s “the right time to move into personalized and individualized medicine.”
As the industry heads in that direction, too, the pipeline of personalized medicine candidates is growing “huge,” but a potential roadblock lies ahead, insofar as “there’s really not a purpose-built, right-sized manufacturing solution,” Schiel said.
Still, regulatory developments are becoming more amenable to such a manufacturing network too, said Schiel, pointing to the FDA’s work on its Framework for Regulatory Advanced Manufacturing Evolution (FRAME) Initiative, which began in 2022 and has helped clarify the FDA’s thinking on the implementation of decentralized drug production.
“There’s just so many pieces that kind of are aligning around this orbit to say that now is the right time to really try to tackle this challenge head-on and see if we can advance this field faster than it would normally evolve,” Schiel said.
Throwing down the gauntlet
Under the manufacturing platform project, four groups tapped will focus on developing automated platforms for RNA-based drugs that can also perform quality control testing at or near the patient point of care.
These include Centillion Biosciences, which will focus on a system combining cartridge-based tech for DNA and RNA manufacturing with integrated fill, finish, QC and digital process management; HDT Bio, which will work on a platform combining automated DNA synthesis, chip-based RNA production, closed fill-finish and robotics-enabled quality control testing; and Waterfall Scientific, which will work to build an automated, benchtop continuous-flow system that combines proprietary tech “from a consortium of expert organizations” to produce RNA drug products.
Massachusetts General Hospital has also been recruited for the project and will develop a single-use, all-fluidics chip system and control unit hardware for continuous manufacturing and QC testing, while the University of Utah will focus primarily on quality control and has been tapped by ARPA-H to create an “all-in-one genetic medicine testing platform” that can perform full QC testing and lot release within as little as a day.
A crucial consideration in the new ARPA-H project is to bring both the manufacturing and quality control pieces to the table at the same time.
“We tried to really challenge teams to bring a holistic solution,” Schiel said. “So, you have to make a product, you have to release a product, and while often you think of those as two separate pathways, they’re actually connected through the control strategy.”
He added that ARPA-H is hoping to bring forward a network that offers a holistic solution, “along with that digital layer” to allow for electronic batch records, LIMS for analytics and better communication between systems.
While ARPA-H is pledging up to $125 million across the project, Schiel clarified that the agency has “great flexibilities in our contracting mechanisms,” noting that it doesn’t refer to the potential funding as ‘grants.’
“The ultimate goal is that each of these teams develops a system,” he said, referring to the delivery of a holistic solution as the “absolute gold star achievement” for one of the organizations selected for the program.
And although the work will take place on an individual team level to start, “there’s certainly a possible scenario in the future where there is some partnership amongst teams,” Schiel added.
Ultimately, ARPA-H will retain “the flexibility to kind of mix and match,” and to also bring new partners in as the project progresses, he explained.
Regarding the potential release of a drug made on one of these systems, Schiel readily admitted that the quality control component is “definitely my passion,” something that harkens back to his time at the National Institute of Standards and Technology (NIST), where he spearheaded the development of a reference monoclonal antibody known as the NISTmAb—a test molecule that functions as a control standard for biopharma developers.
“The learnings from that are really translating to this program,” Schiel pointed out.
At present, analytical measurements are “happening all over the place,” with multiple operators responsible for multiple pieces of equipment enlisted in the QC process, but these steps are nevertheless “absolutely integratable from an automation perspective,” Schiel said.
“We could take today’s existing technology, highly automate them, and streamline the capability to do that sample processing,” he said, pointing to the potential offered by a “much simplified solution that is more robust, more repeatable, more harmonized.”
He brought that ambition back to the NISTmAb, noting that at that project’s start, “the biggest question was, ‘What is well characterized?’”
But after talking through it at “meeting after meeting” and bringing the community together for feedback, what well-characterized means in the monoclonal antibody space is now “very defined,” Schiel said, adding that “I think we’re starting to get to the point where we can have those conversations in RNA, and we actually are now able to build those highly automated systems that can sort of bring everything together.”
The current RNA production network undertaking will play out in phases, starting with an initial six-month period that Schiel described as “pen-to-paper,” during which companies will work up blueprints and “fabrication-ready templates.” Next up will be a two-year phase 2, which he referred to as the “non-GMP phase” and said would act as a “proof-of-concept capability demonstration.”
“The teams will be bringing together the pieces from each of the individual team members, integrating them into this holistic system, and at the end of that two years, they’ll demonstrate that they can make product of sufficient quality on the system,” he explained.
While he referred to that stage as non-GMP, the goal at that point is to have “a piece of equipment that, with minor translation, could in theory be put into a traditional GMP facility,” Schiel said.
Once the more forward-looking phase 3 of the project rolls around, which Schiel christened the “Holy Grail,” he said that ARPA-H aims to “integrate an enclosed system” that would essentially turn a piece of manufacturing tech previously relegated to designated facilities “into something that could sit in a hospital, in a pharmacy, in a genetic medicines institute, for example.”
On the regulatory front, ARPA-H is in “pretty constant contact” with its colleagues over at the FDA’s Center for Biologics Evaluation and Research (CBER), Schiel pointed out, noting that the two agencies together “brainstorm around the high-level thinking about some of these concepts of what does distributed manufacturing look like.”
ARPA-H is hoping that the large learnings from its RNA manufacturing effort will function as a “training set,” with the eventual plan to hold active listening sessions in which regulators, thought leaders, venture capitalists, companies and more can participate in the dialogue.
Meanwhile, as the manufacturing project takes off in parallel with ARPA-H’s separate RNA-based therapeutic platform challenge, Schiel said the programs have great potential to piggyback off one another.
As the THRIVE project oversees personalized RNA-based therapeutic platform development, “we’re building the manufacturing platform side by side,” said Schiel, noting that “the two actually have very similar intersecting endpoints at each of the phases.”
Describing “huge side-by-side synergy” between the two efforts, Schiel noted that the ultimate goal is “cross-pollination.”