There’s no denying that gene technology research is helping us take great strides in the personalisation of care, with many pharma companies and biotechs vying for the ‘silver bullet’ in the treatment of rare and, increasingly, more common diseases. One emerging player in gene silencing technology is Silence Therapeutics, with offices in London, Berlin and New York.

In May, Silence Therapeutics announced its first clinical data, and here President and CEO, Mark Rothera, and EVP, Head of R&D and Chief Medical Officer, Giles Campion, discuss the company’s clinical programme.

Mark joined Silence Therapeutics as President, CEO and Board Member in September 2020, with three decades of experience in the biopharmaceutical industry including driving the transition of multiple emerging biotech companies from the R&D stage to commercialisation. During his career, Mark has focused on bringing novel therapies to patients and has launched seven orphan drugs globally and he previously served as CEO of Orchard Therapeutics.

Giles joined Silence Therapeutics as the Head of R&D and CMO in June 2019 and was appointed an Executive Director in May 2020. Giles is an expert in translational medicine and a highly experienced biotech and pharmaceutical professional across many therapeutic areas, including cardiovascular and orphan disorders.

In the last ten years we have seen an emergence of companies focusing on gene technology to target rare and chronic diseases – what makes Silence Therapeutics different?

Mark: As pioneers in the design and development of siRNAs (short interfering RNAs), we’re delighted to be in a position where we’re now advancing our clinical programmes, which we hope will lead to a new generation of medicines for people with limited or inadequate treatment options.

Our mentality is very much that of a start-up, in that we’re constantly striving for better ways of doing things. People might be surprised that Silence Therapeutics has around 20 years’ heritage as a company, so although we’re still building our profile with a recent move to add a US presence to our existing European operations, we’re by no means a new kid on the block. We have a wealth of expertise and skills to back up our processes, which means we can effectively and quickly identify and pursue new targets for potential treatment.

Giles: I joined the company two years ago and was immediately struck by the team’s creativity and sense of pride in what they do. We are curious and driven to bring our best to work every day and find better solutions for the communities we serve.

Unlike other companies with gene therapies, our gene silencing technology does not cause permanent changes to DNA and is designed to only ‘hit’ the intended target gene in the liver.

What also sets us apart is that we always bring the patient into the decisions we make and the actions we take. Whatever our role or remit, we share a common motivator: to help.

For those unfamiliar with gene silencing and RNA technology, can you explain a bit more about this?

Giles: Gene silencing is a relatively new treatment technique that makes use of the body’s natural processes to control disease by suppressing or ‘silencing’ specific genes that are associated with certain diseases. In this context, ‘silencing’ means temporarily dialling down a specific gene’s message that would otherwise trigger an unwanted effect.

There are a number of different types of gene silencing methods. We’re focusing on a biological process called RNA interference (RNAi). RNAi is a natural control system that regulates the expression of proteins and protects the body from foreign invaders such as viruses. It was a breakthrough discovery in the field of molecular biology in the late 1990s and the scientists who discovered it deservedly received a Nobel Prize in 2006.

RNA molecules clear up mutations, correct mistakes and attack viruses that have infiltrated DNA. Fundamentally, the treatments we develop are based on RNAi technology, which precisely targets and silences disease-causing genes.
We use a special delivery system called GalNAc that enables the siRNA molecule to be delivered precisely to the cell containing the disease-related gene in the liver. This specific delivery system contributes to the safety and power of this approach.

We are also working on delivery systems for other cells, as siRNA can potentially silence any disease gene in the body. The processing mechanism in the cell contributes to another key feature – a long duration of action.

This ongoing development led to you hitting a big milestone in May 2021 – announcing the first ever data from your clinical programme. Can you tell us more about SLN124 and why this milestone is important?

Mark: That was a big day for us – the SLN124 healthy volunteers study announcement represents the first clinical data from our mRNAi GOLD platform and underscores the promising potential for our technology to deliver precision medicines. It’s something we have been working on for two decades and it puts us firmly on the map in the gene silencing space.

SLN124 is one of our two wholly owned candidates being studied for the treatment of iron-loading anaemias like thalassaemia and myelodysplastic syndrome (MDS). SLN124 aims to ‘silence’ TMPRSS6, a gene that prevents the liver from producing hepcidin, the hormone that controls iron levels in the body. As hepcidin increases, it is hoped that iron levels in the blood will decrease, which could in turn allow more healthy red blood cells to be produced, thereby improving anaemia.
  
In our GEMINI, phase 1, healthy volunteers study, SLN124 was shown to be safe and effective in reducing plasma iron levels and had a long duration of action. Specifically, we observed excellent safety, robust gene knockdown expressed by up to an approximate four-fold increase in average hepcidin along with a 50% reduction in serum iron levels and a durable effect which lasted throughout the study.

Not only are we encouraged by this data for our current programme, it also contributes to a body of evidence for the use of gene therapies in other haematological disorders.
What people new to the field might find exciting is that we believe that early-stage GalNAc-conjugated RNAi programmes have a much greater likelihood of approval versus the industry average, due to the high-quality target identification and lower attrition rates.

What other disorders is Silence Therapeutics investigating treatment for and what else does Silence Therapeutics have in its pipeline?

Giles: Our wholly owned pipeline is currently focused on three therapeutic areas of high unmet need: haematology, cardiovascular disease and rare diseases. In addition to SLN124, we are also investigating SLN360 in individuals at increased risk of cardiovascular disease due to high lipoprotein(a). One in five people are estimated to have high lipoprotein(a) levels, so in terms of the size of the potential treatment population and the scale of unmet need here, we’re looking at blockbuster potential.

SLN360 aims to ‘silence’ LPA, which means the levels of Lp(a) are lowered, and this in turn is expected to lower the risk of heart disease including heart attacks and aortic stenosis, as well as strokes.

SLN360 is being investigated in our APOLLO phase 1 study in people with high levels of, or ‘elevated’, lipoprotein(a).

Broadly speaking, we’re developing a deep pipeline of innovative siRNA therapies – in-house and with our partners – for diseases with a genetic basis. The depth and versatility of our mRNAi GOLD platform gives us the opportunity to address a wide range of conditions in virtually any therapeutic area.

We are using the power of translational genomics to both discover and validate new disease-related genes that we can target. Large databases such as the UK Biobank provide a tremendous insight into the relationship between genes and disease. Everyone talks about the power of Big Data these days and it’s true that approaches that have this type of information attached to them have a much better chance of being successful.

Not forgetting the use of artificial intelligence, which has the potential to greatly optimise the design of our molecules, which need to be customised to the chosen gene sequence. By targeting genes expressed in the liver, our mRNAi GOLD platform has been created to address the underlying source of disease rather than the symptoms it causes.

What does the next 12 months look like for Silence Therapeutics?

Mark: We’re anticipating three phase 1 data read-outs this year for our wholly owned programmes. We believe the opportunity for our GOLD Platform is substantial.

Existing siRNA programmes have only scratched the surface of the liver target space. To put that into context, there are approximately 14,000+ genes expressed in the liver and only ~1% are being targeted by siRNA players currently.

So, our goal is to target two to three Investigational New Drug (IND) applications per year from 2023 through our proprietary and partnered GalNAc programmes. What is encouraging is that the probability of successfully developing a medicine using this type of platform is substantially greater than the industry average.

In order to meet that goal, we’re expanding rapidly across the globe, with a physical presence on both sides of the Atlantic, with headquarters in London, R&D in Berlin and offices in New York. The future for us, and for the unmet need of patients in the disease areas we are researching, is looking promising.

‘Unlike other companies with gene therapies, our gene silencing technology does not cause permanent changes to DNA and is designed to only ‘hit’ the intended target gene in the liver’