How Can We Move RNA Forward In Our Therapeutics Arsenal?

RNA technologies, including mRNA therapeutics, have emerged as a promising drug modality because of their essential role in protein expression and their potential versatility in manufacturing. As a result, RNA is in the global spotlight and is an industry priority because of its use to combat COVID-19.

To help further drive progress, BioPhorum gathered a team of subject matter experts to identify and address the RNA-focused manufacturing challenges. The team’s first deliverable is The challenges of using RNA as a therapeutic or a gene-editing tool.

The paper introduces this critical area and shows its unique challenges, not only those around mRNA therapeutics but how these challenges could negatively impact companies and the RNA industry. The team identified more than 50 challenges grouped into a final list of 15 distinct topics – each of them will be worked on separately by dedicated sub-teams.

The 15 topic areas are (not in order of priority):

1. Defining terminology.
2. RNA drug product (DP) route of administration, dosing strategy and distribution in a patient.
3. RNA pharmacodynamics and pharmacokinetics.
4. RNA-specific critical quality attributes and critical process parameters and links to clinical performance.
5. RNA-specific assays and analytical tools/equipment.
6. RNA-specific reagents and raw materials and associated challenges, e.g., sourcing and use.
7. How does RNA compare against established therapeutic modalities?
8. Operational requirements to establish an RNA platform/DP.
9. Regulatory guidance on RNA.
10. RNA advocacy groups.
11. Contract development and manufacturing organizations (CDMOs) and contract research organizations (CROs) supporting RNA production/manufacturing.
12. mRNA stability, storage and handling, and shipment challenges.
13. Scale-up challenges for RNA drug substance (DS) and DP manufacturing.
14. Cleaning and safety considerations during the use of RNA and associated reagents.
15. Technical requirements and challenges for the use of RNA during manufacture.

We asked two of the paper’s lead authors – Kathryn Black, MSAT manager/business partner (mRNA) at Lonza and Jimmy Chu, senior scientist (mRNA process development) at 2seventy bio – some questions to explore the key areas in more detail.

What topics are demanding the most attention in the RNA development space?

CHU: topic 6: RNA-specific reagents and raw materials and associated challenges is a critical area as the field is new and there are a lot of research-grade reagents and raw materials available on the market. However, we still need sufficient and multiple supply sources to minimize supply risk throughout the drug development process. We also need unified quality standards among those suppliers and appropriate material grades so they can be used in the drug development process with the appropriate quality.

CHU: Linked to this, my second priority area is topic 11: Contract development and manufacturing organizations (CDMOs) and contract research organizations (CROs) supporting RNA production/manufacturing. We see a lot of growth in these fields due to the COVID-19 vaccines, but we still need to establish a mature CDMO landscape and appropriate services because slots are often really hard to find and/or have long lead times. So, improving the services and increasing the number of CDMOs available would benefit these RNA therapies, industry, and patients.

BLACK: Topic 10: RNA advocacy groups is a critical area because I had dealt with skeptics of the science before. It’s important that the everyday person looking to trust science understands how these therapeutics work in their body. And how they can still get sick even if they have a vaccine but that their symptoms will be less severe and their life could be saved. Obvious gaps in knowledge mean people become fearful, especially with the flood of information on social media, which prevents them from accepting these types of therapies. For example, the development of COVID-19 vaccines was accelerated, but their approval was still strictly controlled by different agencies across the globe. People should know that vaccine audits, inspections, and documentation reviews were exceptionally rigorous because it’s a new therapeutic. There shouldn’t be this idea that things were sidestepped or bypassed because we’re in an emergency situation; that just wasn’t the case.

The RNA therapeutics industry isn’t starting from scratch, so are any of the areas slightly ahead of the game?

BLACK: There have been some advances in topic 2: RNA DP route of administration, dosing strategy and distribution in a patient, but there is still lots of progress to be made. The development of lipid nanoparticles (LNPs), for example, is based on the use of liposomes, so encapsulating a therapy inside fatty molecules is quite established. But we’re behind the curve in other areas. For example, COVID-19 clinical trials were the first time we explored dosing strategies. Two shots and a booster? Another booster? An annual shot? I’m not sure we know the right answer yet. We also need to work on distribution in the body and any off-target effects, such as significant delivery of lipids to the liver.

My other thoughts are around topic 12: mRNA stability, storage and handling, and shipment challenges. We know about mRNA stability issues like it needs cold storage and has a short shelf life. “But we still need to increase stability at warmer storage temperatures, extend its shelf life, improve its distribution, and have a vaccine that doesn’t quickly expire.

CHU: I see the impact of the pandemic running through many areas and I think that RNA development could further leverage existing knowledge from other parts of the industry. These include topic 13: Scale-up challenges for RNA drug substance and DP manufacturing, topic 4: RNA-specific critical quality attributes and critical process parameters and links to clinical performance, and topic 11: Contract development and manufacturing organizations (CDMOs) and contract research organizations (CROs) supporting RNA production/manufacturing.

Are there any developments in the cell and gene therapy (CGT) space that can influence RNA as a therapeutic?

Black and Chu think CGT advances would make regulatory agencies more open to mRNA developments, with both industry and agencies learning through increased discussions.

BLACK: Cell therapies went through a ‘fear of the unknown’ stage but are now proving themselves by saving lives. mRNA therapeutics are following a similar trajectory. However, CDMOs must change to handle mRNA compared to general biologics or CGTs. If something hasn’t been manufactured before, the novelty is very exciting, but other teams may be more cautious because of their focus on regulations. For example, do we need new tech transfer procedures for mRNA instead of following a biologic procedure? These talks have started, but we’re not there yet.

CHU: Topic 2: RNA DP route of administration, dosing strategy and distribution in a patient could be a key influence. LNPs, novel lipids, novel targeted delivery methods, and mRNA toxicity will all have a huge influence on RNA advances. And if mRNA is used as a gene-editing tool, once more targets are identified, they could boost the CGT area and have a strong impact on the RNA therapeutic area.

Where are the biggest gaps in the infrastructure for supporting therapeutic RNA?

BLACK: The two biggest holes are an advanced platform process that works for multiple customers and relieving supply chain stress by moving away from some single-use consumables. But if you’re removing single-use, you’re bringing in cleaning, so we need to understand the specific cleaning requirements and suitable agents for these products. So how do we standardize cleaning validation if we move away from single-use?

CHU: In my opinion, supply chain and manufacturing considerations require the most immediate attention. The supply of raw materials, equipment, and CMO availability are still catching up to the exploding demand of RNA therapeutics. A model that could potentially change this would be a one-stop-shop service at CDMOs that runs from starting materials through to formulation.

Will the development of RNA therapeutics be more cost-effective and less time-consuming than biologics and CGTs?

BLACK: RNA therapeutics mean we’re not doing cell culture and fermentation, so that time is saved. We’re talking about an RNA process that takes seven to 10 days, so we’re efficient with our scales and process times. mRNA vaccines mean industry has a unique opportunity to create a totally different therapy by changing just one raw material, e.g., the starting plasmid. We should take more advantage of this.

CHU: I see lots of efficiencies in RNA therapeutics. Manufacturing is already largely a platform-based process and can be easily adopted for multiple constructs. It doesn’t require many development iterations for new sequences and scalability is relatively simple compared to general biologics. The RNA process is also more cost-effective in a way that the manufacturing duration is shorter.

How do you anticipate the development of therapeutic RNA will change industry?

BLACK: Inspectors’ mindsets must differentiate between traditional pharmaceuticals and mRNA issues and needs. Also, CMOs need to develop specific procedures for these types of therapies, as they have done for CGTs.

CHU: The personalized medicine aspect is an innovative way of looking at therapies,” said Chu. “This could transform industry – from how we think to how medicines are made.”

Moving Forward

This Q&A discussion illustrates that there have been significant progress and developments in the RNA field. It highlights alignment on many critical topics but differences of opinion on priorities, which may depend on an organization’s current point of view and maturity in the sector. Whatever the reason, it supports the need for collaborative discussions to get the wider industry perspective and achieve some consensus.

Now is a perfect time for all parts of industry, including regulatory agencies, to come together and discuss its challenges and streamline the development of RNA. This will maintain the current focus on this technology, both as a therapeutic and part of the gene-editing toolbox.