The External Partners Delivering The Components Of RNA Therapies

By Louis Garguilo, Chief Editor, Outsourced Pharma

During my discussion with two executive members of the relatively new Society For RNA Therapeutics (SRT) they mentioned external partners and equipment providers I wasn’t overly familiar with.

For DNA templates:
DNA Script
Elegen
Genscript

For generation of mRNA:
Nature’s Toolbox
Trilink
Houston Methodist RNACore

For encapsulation of mRNA:
Helix Biotech
HDT Bio
Precision NanoSystems (now part of Cytiva)

Then there were CDMOs mentioned by SRT's John P. Cooke, M.D., Ph.D., President & Board Member, and Andrew Varley, Secretary, I knew well.

Among those are some listed on some of the 25-plus FDA approved RNA-based (or oligonucleotide) therapies, including:

Agilent Technologies
Baxter BioPharma Solutions
Catalent
Lonza
Rentschler Biopharma

Although SRT focuses on translational R&D, providing public/professional education and training guidelines, and establishing best practices for the creation of RNA therapeutics, I had these two professionals focus on supply chains and outsourcing. 

Where Is RNA Outsourcing At?

Cooke is Director, Center for RNA Therapeutics / Chair, Dept. of Cardiovascular Science, at Houston Methodist; and Varley, Founding Director & Head of R&D, UBC RNA & Formulation Core.

They say “RNA-based therapeutics” have become a diverse field of application. Outsourcing the components of these programs is challenging.

Cooke and Varley note the efforts it may take to assemble an entire supply chain can soak up time and resources; which partners to select depends on what specific area of RNA development you are pursuing.

Of the FDA-approved RNA-based therapies, antisense oligonucleotides (ASOs) represent the largest share, targeting specific RNA sequences to alter protein sequence or expression for rare genetic and neurological conditions. 

Small Interfering RNAs (siRNAs) represent RNA interference (RNAi) drugs designed to silence specific disease-causing genes, predominantly for metabolic and rare liver conditions, whereas mRNA drugs are protein encoding, and used for vaccines and other therapeutic proteins.  

mRNA drugs comprise formulations utilizing lipid nanoparticles to deliver messenger RNA instructions, notably licensed for infectious disease prevention.

Cooke says in no way are advancements and new areas of RNA application and development slowing down. He did, though, generally divide RNA therapeutics into two manufacturing worlds:

“Smaller RNAs – such as siRNA and antisense oligonucleotides (ASOs) – are generally produced through chemical synthesis. Protein-encoding RNAs, including mRNA, circular RNA, and self-amplifying RNA, follow an entirely different manufacturing pathway based on in vitro transcription from DNA templates.

“Those different therapeutic classes also require different manufacturing expertise,” Cooke says.

Most Outsourced Pharma readers may be involved with the larger, protein-encoding RNA therapies moving through development.

Those programs frequently require multiple specialized external partners:

• One supplier may produce plasmid DNA;
• another perform the in vitro transcription into RNA;
• a third develop or employ critical analytical release assays;
• and yet another may specialize in lipid nanoparticle encapsulation.

This list is not exhaustive.

There are a handful of CDMOs claiming they perform several of these steps, but neither Cooke nor Varley are certain that in practice any provider currently can perform every step.

And so today we find “companies that just make plasmid DNA; those transcribing that into RNA; companies to perform qualification; others that do the encapsulation ... and those who say they can do it all."

For small biotechs these varying "options" create outsourcing pressures.

RNA developers find themselves devoting more time and energy than anticipated to construct an integrated development and manufacturing network, which is perhaps a better descriptor than supply chain.

Varley, whose group at the University of British Columbia operates much like a preclinical CDMO, helps academic researchers and startup biotechs consider all these aspects from prior to launching RNA programs up to just before commercial manufacturing.

“Our experience demonstrates organizations underestimate the manufacturing challenges, beginning with something as fundamental as DNA quality,” he says.

Problems with DNA templates, contaminants carried over from bacterial production, or inadequate quality control early in development can affect the final RNA product long before manufacturing scale becomes the issue, he says.

Of concern, then, is what Varley and Cooke describe as today's yawning analytical gap.

The RNA industry still lacks universally accepted methods for measuring important quality attributes, including double-stranded RNA impurities, and 5’capping efficiency.

Varley says different organizations can analyze the same sample – often utilizing different assays – and arrive at “meaningfully different answers.” Even large, experienced pharma organizations encounter this problem.

Cooke agrees. "There certainly are opportunities in the field for additional optimization," he says, adding that is one reason the SRT was founded – to bring researchers together to establish best practices and improve analytical standards.

Practices and standards that should make their way to the CDMOs you select.

This theme of standardization through collaboration surfaced repeatedly throughout our discussion. Tellingly, both Cooke's program at Houston Methodist and Varley's operation at UBC have evolved in part into something resembling “academic CDMOs.”

Academic CDMOs On The Rise?

Houston Methodist has generated hundreds of RNA constructs while developing its own analytical methods. As Cooke joked, "We have to. You can't get these assays at Kmart."

Smaller biotechs often rely on such academic centers because they lack the internal capability to generate DNA, manufacture RNA, validate product quality, or perform encapsulation themselves.

These "academic experiences" shape the careful advice Cooke and Valey offer RNA start-ups when selecting external partners and considering supply chains.

Varley's first proffered recommendation is that rather than beginning with capacity or price, developers should first understand what manufacturing equipment, formulation technologies, and relevant expertise in each required service area a CDMO holds.

Are their systems compatible with the process already developed, either internally or externally somewhere else? Different lipid nanoparticle manufacturing platforms, for example, may not be directly transferable as programs scale.

Cooke points to an underestimation of “intellectual property surrounding lipid nanoparticle delivery systems.”

Delivery technology, he says, is now a defining competitive advantage in RNA-therapeutics programs, “but also one of our most complicated legal landscapes.”

He suggests companies entering the field work with experienced advisers who understand the IP environment before making long-term manufacturing decisions.

Perhaps overall, what strikes me most is just how much more opportunity remains in the field – Cooke can articulate a multi-faceted RNA future with the best of them.  

But for the greatest of those futures to occur, RNA sponsors must think deeply in terms of assembling development and manufacturing ecosystems, starting at the earliest stages of research and company formation.