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Improving vaccine delivery with N4 Pharma

EPM speaks to Nigel Theobald, CEO of N4 Pharma who discusses the formulation challenges that can occur during drug development and what the company is doing to improve vaccine delivery systems.

We understand that you are developing a new delivery solution for cancer treatments and vaccines based around a novel silica particle – Nuvec. What are the key delivery challenges that you are able to solve?

Current vaccine delivery systems have a number of less than optimal properties. These include:

Many current vaccines require an additional adjuvant to be included in the formulation.  

Nuvec silica nanoparticles have a unique irregular (spiky) surface structure, coupled with polyethyleneimine (PEI), that simply and effectively traps and protects nucleic acid (such as mRNA / pDNA) as it travels to the cells. Once inside the cell, the nucleic acid is released to activate the immune system. Nuvec is also a natural adjuvant so it attracts large numbers of antigen presenting cells which, in turn, leads to a strong activation of T-cells, increasing the level of immune response against the target cancer cells.

Studies so far have shown that Nuvec is well tolerated, even at high doses with no major toxicology findings across rat/mouse in vivo and PBMC/spleen in vitro studies. It can deliver large plasmids up to at least 10,000 base pairs.

All of these points highlight the differences between Nuvec and existing vaccine delivery systems, which indicate that it has the potential to optimise vaccine efficiency, minimise side effects and reduce end user costs. 

How does your technology compare with other approaches that formulation scientists could pursue?

The properties of Nuvec are unique compared with other silica nanoparticles that are also being explored as delivery systems. In particular, we have developed, and have filed patents on, the unique structure, in which spikey outgrowths of silica are formed on a central core. These outgrowths increase the surface area, maintain a negative charge and probably contribute to the interaction with the target cell surface. Most other silica nanoparticles contain their payload in pores or in the hollow pore, which limits the molecular size and amount of the molecules that can be loaded.  By making use of the large surface area, Nuvec can deliver full length mRNAs and large plasmids, and has a high capacity – up to 10% by weight of nucleic acids.  

Where did the initial idea for Nuvec come from and how did that evolve into a commercially-viable opportunity?

The Nuvec technology is licensed from the University of Queensland ("UQ"). Mesoporous silica particles have been used for a while as a delivery system whereby a payload is absorbed into the centre of the silica particle.  The original UQ technology worked in this way. As with other systems mentioned above, the particles were hollow and had pores that allowed sub unit vaccines to enter the particle through the pores, but these pores were small enough to keep the payload inside the particle and only let it release slowly over time. This solution was suitable for sub unit vaccines, but would not work for DNA and mRNA, which are too big to pass through the pores. We therefore developed Nuvec to grow spikes in between the pores, allowing DNA and mRNA to be captured. Nuvec has been specifically developed to work by capturing the payload on the surface of the particle, but still giving sufficient payload protection so that it can be safely and effectively delivered into the cell. The spikes give Nuvec some of its distinct advantages.

Tell us a little bit about the development process so far and any key achievements or setbacks you have experienced?

Our initial understanding of the manufacturing process was provided by the creators of Nuvec at UQ.  As is normal in such collaborations, we have now transferred the technology to a contract research organisation (CRO) and have developed a controlled process to make consistent multi-gram batches. Process control and optimisation are now under refinement and our plans to move towards GMP grade material suitable for regulatory standard non-clinical/clinical trials are well in hand. The manufacturing process is relatively simple and no problems are foreseen in transitioning to quality product. 

With respect to biological data using DNA loaded Nuvec, multiple in vitro experiments have been conducted successfully, and experiments in vivo have demonstrated immune responses against both mRNA and DNA-encoded proteins delivered by Nuvec.  However, like many other delivery systems in development, the relationship between in vitro and in vivo data is not always simple. In particular, our in vivo data demonstrated a lack of consistency between animals in each study and between studies. Evaluation of the formulation injected in the in vivo studies, showed that under the experimental conditions used, the Nuvec was agglomerating to forms clumps. Individual Nuvec particles are around 200nm in diameter, but the clumps consisted of multiple particles resulting in a mean size greater than 1,000nm. There is an optimum size that cells can take up and the clumps in vivo clearly exceed that. We now have an ongoing programme, which is progressing well, to resolve this issue and provide an in vivo formulation with a mean size in the 200nm range.

What next steps are planned? Will we see Nuvec  in the clinic soon?

Once the formulation work has been completed to reduce the mean particle size, we will repeat our in vivo studies and also undertake an oncology efficacy study. This will then give us a full data pack to share with prospective partners who are developing novel nucleic acid products to license Nuvec as part of their clinical development. We will also be undertaking GMP grade manufacturing tech transfer so we are able to provide partners with GMP grade material for clinical studies. The timing of getting to clinic will depend on the partners, but, all being well, we should be ready for the clinic in 2021.

Based on your own learnings, is there any advice that you would give to other SMEs developing pharmaceutical solutions?

As a small start-up with an innovative technology that has huge potential as a novel delivery system, but with limited resources, the ability to initially work with much larger research collaborators to undertake in vivo testing using their own nucleic acids was extremely tempting. The downside is that you lose control of your development programme as collaborators insist on testing the system ‘their way’, before you have had chance to fully optimise it. However, without our own access to proprietary nucleic acids, this was the only way we could accelerate our learning with the resources available. 

These early research collaborations have been invaluable in helping us understand how Nuvec behaves, but it is now vital that we bring the next phase of development in-house. The strong early promise that Nuvec showed in vitro was sufficient to get partners to undertake that initial exploratory work. Once we complete our optimisation work, we will be in a much stronger position to actually license Nuvec to partners for full pre-clinical investigation. 

The early challenge for an SME is between funding and building the expertise for the development work you need to do in-house, versus accelerating that development by external collaboration. The key learning for me is to make sure you fully manage the expectations of all your stakeholders as the programme develops.     

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