Inside NeoVac's LNP Formulation Strategy: Challenges, Innovation, And What Comes Next

A conversation with Jan Egberts, MD, CEO, NeoVac

In this editorial Q&A, Jan Egberts, MD, NeoVac’s new CEO, shares insights into the scientific, regulatory, and manufacturing hurdles shaping the company’s mRNA therapeutic pipeline with Life Science Connect’s Michael Soloway.

What roles are artificial intelligence and machine learning playing in NeoVac’s formulation development process? How do you see the industry currently working with AI to improve our ability to design lipid nanoparticles (LNP) today, and in what ways are these technologies still falling short?

Egberts: Although AI is extremely important in research and development for a great number of fields, the potential impact of AI for LNP development work is questionable. One reason is the complexity of the technological and biological systems in combination with limited availability of comparable data for training of the AI tools.

AI normally requires very large data sets to be trained, which are not available for LNP development. Publicly available formulation data is mostly generated from different laboratories under different conditions, and therefore comparability is limited. Furthermore, while biological data from in vivo studies are valuable, clinical evaluation in patients would ultimately be required. Such directly correlated data is available only to a very limited extent.

However, more classical computing approaches, including molecular modelling and simulations, can in fact play an important role. For example, for better understanding and control of the self-assembly processer of LNPs, molecular modelling has proved to be valuable. In general, basic research to generate better understanding of fundamental coherencies of LNP formation is particularly important.

In this context, it may be worthwhile to mention that AI can in fact play an important role in different fields related to the development of mRNA therapeutics. For example, AI can help improve approaches in bioinformatics, where, for tumor immunotherapy, neoantigens need to be identified. This will help to improve personalized nanomedicines for cancer therapies.

We think that better understanding of the underlying scientific coherencies will be more important for development of improved new products than the application of AI only as a tool.

How are you approaching the challenge of formulating for multiple delivery routes - particularly as the industry moves toward patient-centric administration like subcutaneous, oral, and inhaled delivery?

Egberts: In fact, different application routes, as well as different types of RNA cargo and different approaches for pharmaceutical intervention, each require tailored formulations. In addition, different and new technologies are required, like devices for inhalation delivery. Therefore, we focus on selected routes of application. This limits the efforts and resource requirements for developing multiple different technologies in parallel. Currently, intravenous and intramuscular delivery are the lead application routes we are focused on.

What are the current limits in achieving these different formulations with LNPs, and what will be a scientific and/or technical advancement that will help unlock these different formulations?

Egberts: In principle, for the parenteral application routes, intravenous (IV) and intramuscular (IM), similar formulations can be applied. However, a general technological challenge here is stability. Better buffer systems and lipid combinations to allow for improved stability need to be developed. Differences between the formulation requirements for IV versus IM applications may relate to biodistribution and immunogenic characteristics, as the intended route of pharmaceutical intervention is often a different one.

Formulations for alternative application routes, like subcutaneous, oral, or inhaled delivery, are very interesting for future product development, but they create additional technological challenges. This is because devices (e.g., inhalers, microneedle arrays) or more complex dosage forms (e.g., powders to be filled in capsules for oral delivery) are involved. The required formulation development work needs to be done in addition to and in alignment with technological device development, which leads to elevated complexity, timelines, and costs.

What are the biggest differences between how the FDA and EMA are regulating LNPs? What challenges do these differing regulatory approaches pose for companies working in the broader LNP space?

Egberts: There are in fact certain differences between FDA and EMA, but also with other regulatory agencies, like MHRA in U.K., which need to be taken into consideration. It is important in this context that, currently, efforts involving different authorities, including FDA and EMA, are ongoing to harmonize the requirements for approval of novel LNP products. Such harmonization will be of great help for companies and institutions, because the identification and definitions of the regulatory requirements still require alignment between all parties involved. Such knowledge will provide an important basis for the efficient development of future products.

What are the biggest questions we have today relating to LNP quality?

Egberts: This question refers to what is usually denoted as the critical quality attributes (CQAs), and these are to be covered by the panel of quality control (QC) assays. These panels are applied to the LNP drug product. There are some GMP parameters that are generally accepted and not up for debate. These are in accordance with the general criteria for pharmaceutical products, including content, purity and integrity of the mRNA cargo, and particle characteristics such as size and charge.

There are still open questions — particularly about how to define and assess quality attributes that arise from the colloidal nature of LNPs. These aspects have not yet been appropriately addressed. While there is an emerging consensus regarding the criteria for individual components that constitute the drug product (e.g., the mRNA and the lipids), this is less established for the overall nanoparticles. LNPs are complex, multicomponent systems. They self-assemble from the different molecular moieties to the nanoparticles driven by electrostatic and other types of interactions, which sensitively depends on the boundary conditions during formation. Their properties depend on the manufacturing process, buffer, and storage conditions. Therefore, we need to get better control over particles of different sizes, structure, activity, and stability that are present in the product.

Another aspect that deserves more attention is the fact that the conditions inside the particles can be rather different from those in the surrounding buffer, which influences the stability and activity of the drug product. For example, it is known that the pH inside the particles is different from the pH of the surrounding buffer. Molecules are in very close contact with each other under these altered conditions, which influences their chemical reactivity and stability.

We are working together with our partners in our research to better understand and control these coherencies. We are convinced that this will help us develop our new products faster and more efficiently.

What emerging analytical technologies are becoming the most important in our quest to better understand the quality of our LNPs?

Egberts: We think there is a need for technologies to gain improved and more quantitative insight into particle size, distribution, and (size-dependent) structural characteristics. These are important parameters indicative of quality, but they are not covered by the standard control panels. In principle, there are several approaches that potentially could provide more detailed information regarding the size and distribution profiles, but so far, none of these have become part of the standard QC panel for LNPs. One reason may be the lack of standardization and comparability for results, which results in variances between different sites and under different conditions.

Another important parameter is structure. This has been recognized by many laboratories and companies. Small angle X-ray scattering (SAXS) is regularly used by many laboratories for structure analysis. However, one of the limiting factors is again the lack of standardized protocols to allow comparability between the results from various laboratories.

In our own development work, we use methods for improved control of size distribution profiles. We combine these with SAXS measurements to also obtain size-resolved structural information. The experimental protocols we are developing are aligned with the requirements according to QC lab standards. We are confident that these will be suitable for widespread application in advanced characterization and quality control of LNPs. For certain questions, we combine the SAXS and small angle neutron scattering (SANS) experiments, which provide additional information regarding the composition of the nanoparticles and certain characteristics of shape. This can, for example, be used to glean information on particles with a more complex architecture, like a core-shell organization or a certain shape. Many next-generation LNP products use such architecture to improve activity, for example, for improved targeting. One specific task in this context is using LNPs that have been functionalized with ligands for binding receptors at the target cell membrane (tLNPs). These additional dedicated quality control assays need to be developed further. They characterize parameters like density, distribution, and orientation of the ligands at the nanoparticle surface. This will be one of the prerequisites to bring such products into clinical development and to develop through licensing.

Personalized medicine is driving demand for smaller batch sizes and variable formulations. How is this affecting your manufacturing and formulation development approaches?

Egberts: We are developing manufacturing approaches for different batch sizes. Ideally, we’ll develop manufacturing routes that allow for seamless upscaling from very small to very large batch sizes. This is, for example, the case when fluid path systems with an identical mixing device are used and larger batches are simply obtained by increasing the manufacturing time. We are testing different manufacturing technologies that are available from CDMOs, but we are also developing our own proprietary manufacturing techniques. This provides us the freedom to select the manufacturing technology according to the requirements of the product to be developed.

Looking ahead to 2026–2030, which therapeutic areas or formulation challenges do you see as the biggest growth opportunities for your business? Which will be the most challenging?

Egberts: At NeoVac, we see a significant growth opportunity in the field of vaccines against infectious diseases — initially focused on viral infections and eventually expanding to bacterial and therapeutic vaccines. With the successful completion of our Phase 1 clinical study of our COVID-19 vaccine, we have demonstrated both efficacy and a superior safety profile compared to currently marketed COVID vaccines. This enhanced safety profile is a key advantage for vaccines targeting a broad range of viral infections. While efficacy can be demonstrated by many products, we believe our improved safety profile gives us a unique technological edge. We expect regulators to place increasing emphasis on safety as a differentiating factor — especially now that we are no longer in a pandemic context, where urgency previously allowed for different risk-benefit considerations. This is particularly relevant for populations such as children, immunocompromised individuals, and patients in poor general health, where safety will become an essential prerequisite.

We are also working on vaccines against bacterial infections. These could be of extreme importance for protection against hospital pathogens, for elderly and immunocompromised patients, in particular. There is an increasing risk of acquiring healthcare-associated infections during hospital interventions. These pathogens often display resistance to multiple antibiotics. Consequently, there is a serious health risk for these patients. A vaccination against such pathogens prior to an elective intervention such as a hip or knee replacement could significantly reduce the risk of such infections.

Further to that we are also working on next-generation mRNA-based cancer therapeutics, including improved approaches for therapeutic vaccination against tumors. Generally speaking, with our lipid and LNP technology, we can serve all potential applications for mRNA-based pharmaceutical intervention. This includes innovative approaches in multiple fields such as immunotherapy, autoimmune diseases, gene editing, and in vivo CAR T cell therapy. Due to our limited internal resources, we are working with partners who bring their specific expertise to these fields.

About The Expert:

Jan H. Egberts, MD, has over 30 years of experience in the pharmaceutical and medtech industries, most recently as the CEO of his own family office, Veritas Investment. Dr. Egberts is past chair of more than 10 privately and publicly held companies including ViroClinics (sold to Serba), Photocure ASP, and Nordic NanoVector ASP and EndoSense (sold to St Jude Medical). He currently serves on the supervisory board of the European Nuclear Reactor Group for Medical Isotopes, NRG/Pallas, as well as several privately held companies and foundations. Prior to Veritas Investments, Egberts served as CEO of OctoPlus, which he sold to Dr. Reddy’s and Agendia. Prior to these roles he initiated the leveraged buyout and subsequently led J&J’s surgical drapes and gowns division which was merged with Molnlycke Healthcare and ultimately sold to Apex. He also served as a senior industry advisor for 3i Group. Egberts graduated from Erasmus University Medical School in the Netherlands and obtained his MBA from Stanford, after which he worked as a management consultant for McKinsey.