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Discovery & Development Drug Discovery, Formulation, COVID-19, Vaccines

Reaching for RNA

Back in 2020, etherna scored around US$36 million (34 million euros) in financing. The plan? To develop mRNA therapeutics using its proprietary TriMix technology – a mix of three mRNA molecules that can circumvent some of the challenges in immunotherapy drug development. Specifically, TriMix enhances the activation and maturation of dendritic cells, stimulates processes to active helper T cells, and promotes activation of cytotoxic T cells. The company believes that TriMix could form the backbones of both cancer vaccines and localized tumor treatments.

In 2019, the company started a new trial, but then the COVID-19 pandemic threw a spanner in the works. Many companies had to put development plans on hold as trials ceased. But now, it’s full steam ahead at etherna. Here, we speak with CEO Bernard Sagaert about the company’s focus, the impact of the COVID-19 pandemic, and the manufacturing challenges in the field.

Meet Bernard Sagaert

Did you always have an interest in science?

Yes – but I was also interested in business. I wanted a career that would combine both aspects. I went to pharmacy school because it gives you a very broad view on medicine, but I never had any intention of working in a pharmacy. I absolutely wanted to go into business, which is why I chose a sales function role early. In time, however, I did gain experience in various technical areas, such as regulatory quality, batch release, and so on – all of which is very useful for eventually running your own company. It really helps if you have the experience that allows you to talk about anything – whether it’s research, manufacturing, QC, distribution, legal, and so on!

Are you still involved with the science aspects today?

Today, I surround myself with great scientists and I encourage collaboration between them, but I don’t really consider myself to be a scientist anymore. I focus more on the operations side of the company. My role is to direct the science and to help with decision-making. Scientists will work on things that they find scientifically interesting, but it’s very important to direct them to things that balance scientific interest and business needs.

What are the most important lessons you’ve learned in your career?

Making mistakes is something that should be allowed – these are the moments where you learn the most.

You can also learn a lot at small companies. I’ve worked with both big and small companies, but working in small companies has many advantages. You may not reach a very high, professional level but you will get lots of experience in different areas. For me, this has helped me to continuously learn and given me the experience to make good decisions.

What’s the Etherna backstory?

etherna launched in 2013, but the true story begins more than 30 years ago (one of our key people has 30–35 years in the RNA field). We are a spin out from Vrije Universiteit Brussel (VUB), and he worked in the lab of the founding professor of the company, Kris Thielemans. Very early on, they were working with RNA in an ex vivo setting where dendritic cells were treated with what today is our TriMix technology combined with tumor-specific antigens. The results in melanoma with this product were very good, which kicked off the foundations for etherna.

In fact, data from our early melanoma trials in 2011-2013 show similar clinical efficacy compared to the recent phase II trial results in late-stage melanoma from Moderna, which proves that the activation of dendritic cells and re-administration of dendritic cells in a personalized can be really successful.

What else is the company working on?

In 2019, etherna started a new arm in its clinical trial – but we all know what happened next… Many clinical trials had to temporarily stop because of the COVID-19 pandemic.

In 2019, we also started the development of two new products. One was an LNP platform delivered intravenously for use in HPV 16-positive late stage-cancers in combination with anti-PD-1. This is now ready to start clinical trials – and we have clinical trial applications approved so far in four countries in Europe.

The second is currently still in the preclinical phase and is an LNP designed for direct tumor injection with a very specific payload to turn “cold” tumors into “hot” tumors that can be recognized by the immune system – allowing it to destroy the tumor as well as metastases in the body. Tests in animals have been successful so far.

Once the COVID-19 pandemic began, there was a need for an intramuscular prophylactic vaccine platform, which we have now developed.

How has the COVID-19 pandemic changed the RNA field?

The COVID-19 pandemic has opened many doors for the future of RNA. Having such a large number of people treated safely with RNA has really increased everyone’s confidence levels with the technology, particularly for prophylactic vaccines.

However, although we definitely learned a lot about RNA from efforts during the pandemic, there is still a lot to be done on the manufacturing front. During the pandemic, scale was urgently needed and quickly supplied; now, there is ample production capacity available for mRNA manufacturing, but the purity of RNA can still be improved. With the COVID-19 vaccines, we saw high levels of reactogenicity, which resulted in side effects. We may be able to avoid this reactogenicity by using purer RNA.

We also need to further boost the expression of the RNA – and that needs to be addressed right at the start of manufacturing. When you first create your RNA construct, you need to finetune the open reading frame and untranslated regions in the mRNA, also efficient capping of the mRNA can make a huge difference.

There are also questions about batch sizes, which were necessarily large for COVID-19 – but that was an unusual scenario. It’s clear to me that batch flexibility will be increasingly important as more RNA therapeutics are developed. To that end, we’ve launched a collaboration with Quantoom Biosciences to develop equipment that is suitable for both small and large batches. Continuous manufacturing could be the answer

What other knowledge gaps are there in RNA?

COVID-19 vaccines are becoming commodity products, but they are not a commodity from a knowledge point of view. There are many questions. I find that customers have questions around what RNA should look like and how the construct needs to be made. Is it better to use PCR-based DNA? Plasmid DNA? Doggy bone DNA? What capping should be used? What is important in the vector used for the mRNA production?

There is also confusion about what is expected from the regulators and what quality control is needed. In some cases, customers do not understand the different demands of different clinical trial phases. We’ve created freely available buyer’s guides that cover many of these questions, including the difference between research-grade RNA and GMP-grade RNA, cap systems, storage, and delivery.

What lies ahead for the future of the field?

RNA could allow us to tackle many diseases that are currently very difficult to treat by enabling more specific targeting to certain cells. The area is full of promise and many small-scale biotechs are generating exciting results. But what keeps many of us awake at night is the accessibility of funding. We need more investors in the industry to get on board with RNA.

Another issue is attracting the right talent – the talent pool in this industry is very small and many companies are fishing in the same pond.

If you could change one thing about the pharma industry, what would it be?

I would like to see a greater focus on improving general health by preventing people from getting sick in the first place. Encouraging people to live healthy lives should be an important priority in the industry, as well as detecting health problems earlier. It’s much easier to treat diseases in an early rather than late stage.

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About the Author
Stephanie Vine

Making great scientific magazines isn’t just about delivering knowledge and high quality content; it’s also about packaging these in the right words to ensure that someone is truly inspired by a topic. My passion is ensuring that our authors’ expertise is presented as a seamless and enjoyable reading experience, whether in print, in digital or on social media. I’ve spent fourteen years writing and editing features for scientific and manufacturing publications, and in making this content engaging and accessible without sacrificing its scientific integrity. There is nothing better than a magazine with great content that feels great to read.

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