The Evolving Needs of Therapeutic mRNA Developers

Given the strides medical researchers and therapeutic developers were making, the possibility of commercializing mRNA therapeutics began looking bright about ten to fifteen years ago. However, one of the most pressing issues restricting researchers’ efforts was the lack of a reliable high-purity mRNA supply. There weren’t players that could readily and reliably provide end-to-end mRNA therapeutic process development and manufacturing, including plasmid manufacturing, mRNA manufacturing, and lipid nanoparticle formulation. As a result, negotiating contracts and securing the successful integration of these three critical inputs was extremely challenging, and somewhat erratic lapses in supply constantly jeopardized programs.

Vernal Biosciences was launched to address this fragmented mRNA supply chain, offering end-to-end mRNA therapeutic capabilities under one roof. In the four years since Vernal’s launch, the CDMO community supporting mRNA development and manufacturing has made significant progress —Vernal no longer stands alone as the industry’s only end-to-end mRNA CDMO.

However, as a CDMO exclusively dedicated to mRNA therapeutics, we have a leg up in helping our clients navigate the next wave of challenges in this rapidly growing yet reasonably immature sector. With the mRNA supply chain in a much better place than four years ago, we find ourselves leveraging our expertise to help innovators navigate the unestablished and evolving regulatory environment, the need for next-generation analytical capabilities, and providing right-sized operations.

Despite extremely rapid emergency approvals amid the COVID-19 pandemic, the regulatory pathway for approving the multitude of mRNA therapeutics currently in various phases of development is far from established. Global regulators, innovators, and CDMOs worked together to ensure safety during the emergency and are now collaborating under more normal conditions to develop a regulatory framework that will support mRNA approvals for years to come.

One issue at the heart of mRNA therapeutics’ regulatory future is their classification–gene therapy, biologic, or a category yet to be established. Some believe that, based on their mechanism of action, mRNA vaccines and therapeutics should be considered gene therapies. However, others argue that mRNA drugs should not be classified as gene therapies because they do not alter the genome.

Another complication is that the FDA classifies drugs according to how they are produced. mRNA is manufactured via in vitro transcription (IVT) and is considered a biologic—the purview of the Center for Biologics Evaluation and Research (CBER). However, synthetically manufactured RNAs, such as small interfering rNA (siRNA), microRNA (miRNA), antisense oligos (ASOs), and aptamers, are regulated by the Center for Drug Evaluation and Research (CDER).

It is easy to see a world where biologically produced and synthetically produced mRNA would benefit from being under the same regulatory umbrella, not to mention the many other factors that need to be ironed out for the regulatory pathway to mature.

The mRNA regulatory landscape will evolve, but advancing mRNA programs today requires a great deal of expertise, experience, and open communication channels with regulators. Vernal’s exclusive dedication to and focus on mRNA therapeutics allow us to provide the support needed to advance our clients’ programs despite the uncharted waters.

While mRNA therapeutics and more traditional biologics have analytical requirement commonalities, the analytical demands of mRNA are quite a bit more complex, and innovators are well-served to have ample access to the expertise required. Of course, both therapeutic classes require characterization of quality attributes that will impact the product’s safety and process-related impurities–host-cell proteins for protein therapeutics and genetic impurities like truncated transcripts or incorrect DNA template for mRNA.

However, mRNA has differing analytical needs from protein-based biologics simply because mRNA manufacturing has different process steps, such as in vitro transcription (IVT) and lipid nanoparticle formulation.

Yet, the big difference is the need for robust discovery and early-phase analytics for mRNA development programs. Typically, analytical requirements are modest for early-phase protein therapeutics because molecules can demonstrate target engagement and a desired therapeutic effect well before they are optimized. But mRNA products undergo biological processes like cellular uptake, endosomal escape, and protein translation. The characteristics governing these processes must be understood and effectively characterized before any therapeutic effect can be observed at all.

Analytical requirements will also evolve as regulatory guidance solidifies. Innovators need a CDMO partner to keep pace with changing requirements and will benefit from one working with regulators to influence the emerging regulatory expectations.

Thankfully, the community of mRNA CDMOs is more established than just four years ago, but innovators must consider the type of partner that will best serve their needs. It goes without saying that innovators require a CDMO with extensive mRNA knowledge and experience. Additionally, we highly recommend selecting a CDMO partner with end-to-end capabilities to avoid the supply chain coordination difficulties developers experienced before integrated mRNA manufacturing partners existed.

However, innovators can still encounter scheduling issues even when working with CDMOs with end-to-end capabilities, as operations may not be centralized in one facility–pDNA, mRNA, and LNP could be produced in different facilities on multiple continents, for example.

Additionally, many innovators require a flexible CDMO partner so their program is not derailed when delays or other changes occur. Some CDMO operations are simply more nimble than others, and the true extent of a CDMO’s flexibility is often difficult to determine through the sales and negotiation process alone. But conversations with industry colleagues and the CDMO’s other clients are usually quite insightful.

A comprehensive discussion of the challenges facing mRNA therapeutic developers obviously cannot all be addressed in one reasonably brief article. However, as the core supply chain for the reliable delivery of therapeutic mRNA has strengthened, Vernal Bio has turned its sights toward the next wave of challenges, including advancing programs despite lacking a proper regulatory foundation and strengthening platform analytical technologies.

We also increasingly find ourselves helping our clients navigate the intellectual property maze created during the frenzied days of the COVID-19 era. We’ll share thoughts on this issue in a future article. In the meantime, the Vernal Bio team will continue applying our talents and efforts to supporting innovators working to capitalize on the incredible promise of mRNA. If we can help you with your program, please contact us.