Trading update and capital markets presentation

1 December 2014

Silence Therapeutics plc

Trading update and capital markets presentation

Silence Therapeutics plc, AIM: SLN ('Silence' or 'the Company'), a leader in the discovery, development and delivery of novel RNA interference (RNAi) therapeutics for the treatment of serious diseases, announces a trading update for the 22 week period to 1 December 2014.

The Company will also be hosting a capital markets presentation today for analysts and investors at which no further news or material information will be disclosed.

Along with a major technological achievement in messenger RNA replacement therapy, announced separately today, Silence has made material strides towards becoming a drug development company. It now has a genetic toolkit which can, in pre-clinical in vivo animal models, modulate gene expression up as well as down and unique delivery systems to a variety of organs and cell types. In addition, it has a well-established and embedded algorithm for pre-clinical drug development with clear go/no-go milestones.

Translational team - transition from technology to product company

The translational medicine team is working to quickly translate Silence's technology into therapeutic clinical product candidates. Comprising medical doctors, biologists, business analysts and consultant key opinion leaders, this multidisciplinary team is particularly focused on collaborations with leading academic institutions which complement internal expertise and develop new models of study. Current collaborations include the University of Oxford, the University of Cambridge, the Charité Hospital in Berlin and IDIBAPS, a leading Spanish research institute. These partnerships reflect the need of academic centres to access our genetic toolkit in order to further their cutting edge research.

As the technology advances, the translational team will be applying these potential drug candidates to suitable, commercially viable indications. Progress with the increasing activity in our pre-clinical engine and also the implementation of our multiple shots at goal programme is set out below:

· Atu111

Silence is reviewing plans for drug candidate Atu111, which targets the inflammatory agent (Angiopoietin-2) in the lung vasculature. Potential paths to the clinic are being evaluated in acute lung injury and loss of barrier function in infection and inflammation. Evaluation of alternative target(s) is also ongoing in parallel, as well as the combination of several siRNA payloads to multiple targets to fully realise the potential of our liposomes.

· Pulmonary Arterial Hypertension (PAH)

Silence commissioned rodent studies at William Harvey Research Ltd at the University of London. Substantial hemodynamic benefit and reduced vascular remodelling were observed in the disease model treated with our lung-specific formulation for endothelin-1 inhibition. This result is highly encouraging for Silence and PAH will continue to be investigated as a promising therapeutic area. PAH drugs have sales of over $4bn worldwide. However, PAH has a median life expectancy from diagnosis of only seven years, demonstrating the level of unmet need.

· Pre-eclampsia

Silence is working closely with the Nuffield Department of Obstetrics and Gynaecology at Oxford University to apply the Company's systemic vascular delivery for pre-eclampsia. This technology is ideally suited to tackling the leading cause of premature births. Pre-eclampsia generates a huge burden on health services, both around birth and from long-term disability. The total cost of preterm birth to the public sector in England and Wales was estimated in 2006 to be £3bn.

· Lung cancer

In collaboration with the Biochemistry Department at the University of Cambridge, Silence's formulations are being tested in genetically engineered rodents that spontaneously develop tumours. These studies will allow further profiling of the delivery systems in representative models of tumour microenvironment and vasculature, as well as evaluation of RNA payload delivery to cancer cells.

· Liver indications

Studies into acute liver injury and fibrosis at the University of Rostock have produced compelling data in preclinical mouse models. Research is also under way at IDIBAPS in Barcelona, investigating portal hypertension, liver fibrosis and regeneration. The potential for siRNA therapeutics in paracetamol-induced liver failure is also being explored.

· Tumour angiogenesis 

Silence has produced in-house data on pancreas cancer xenograft in vivo models, showing substantial tumour burden reduction. A collaboration to explore this research further is under way, focusing on tumours resistant to current anti-VEGF therapies.

· Ocular melanoma

A study is being assessed into the use of drug candidate Atu027 in ocular melanoma, a rare, highly metastatic cancer. This study will be a further characterisation of this anti-metastatic drug.

· Fibrodysplasia Ossificans Progressiva (FOP)

FOP is an ultra-rare highly debilitating disease that dramatically reduces life expectancy. The unmet medical need for FOP patients is huge as there are no available treatments. The ability of Silence to target endothelial cells and inhibit mutant gene expression could potentially slow or prevent pathological bone formation.

· Radiosensitisation

Given the essential role of the tumour vasculature in the observed response to radiotherapy, the Company is evaluating the use of its delivery systems and siRNA payloads to increase cancer response rates to radiotherapy and potentially reduce the required doses.

· Ischemia/reperfusion injury

Silence is exploring the use of its AtuPLEX delivery system to deliver siRNA payloads to the vasculature of donor organs in order to improve function following transplantation. These studies will be carried out by external collaborators that have developed relevant models of study.

· Vasculitis

Vasculitis is being investigated as a potential indication suited to siRNA technology. The therapeutic effect of Silence's agents will be studied in both pulmonary and renal vasculitis, using mouse models developed by collaborators.

· Cardiopulmonary bypass

An academic collaboration is in progress to study the potential of Silence technology to prevent the detrimental effects of cardiopulmonary bypass surgery in the microvasculature integrity and blood flow.

Delivery systems

In April, Silence confirmed that its DACC delivery system achieved knockdown of target genes in the lung vascular endothelium of non-human primates (NHPs). Further profiling of DACC has been done to optimise dosing and infusion rates and to deepen the understanding of DACC's translatability across species. Parallel studies are in process for the new generation of AtuPLEX, the systemic delivery system for vascular endothelium. Important progress is also being made in delivering RNA payloads to macrophages, key players in the immune system.

As well as a significant internal drive towards better RNA delivery, external technologies are also being continuously evaluated against Silence's benchmark liposomal systems.

microRNA therapeutics

Building on its expertise in siRNAs, the Company is also using its delivery capabilities to deliver microRNA (miRNA) mimics and inhibitors. Anti-tumour activity is being seen in xenograft models and it is currently being assessed whether the miRNA division should remain an internal project or would be better suited as a standalone entity.

Clinical programmes

In July, recruitment was completed for the Phase 2a safety trial using Atu027 in combination with gemcitabine for pancreatic cancer. This programme is on schedule for review in Q2 of 2015. At this stage the safety profile looks encouraging for long-term treatment.

The University of Birmingham remains on track to recruit patients for its Phase 1b study in head and neck cancer using Atu027 in combination with best treatment. For Silence, this will be an important opportunity to establish a therapeutic biomarker.

Outlook

RNA therapeutics is maturing rapidly as a technology and peer companies are reporting good clinical progress. Silence expects to match this success as delivery capabilities are refined and the pipeline grows. At 30 November 2014 the Company had £22m net cash.

Ali Mortazavi,Silence's CEO said;

"Drug development is entering the age of genetic medicine and through our leading technologies and collaborations, Silence is giving the UK and Europe a central role in this ground breaking area of medicine.

"With the ability to modulate gene expression both up and down in pre-clinical animal models, we aim to fundamentally change the timelines, costs and risks of a traditional biotechnology business model. Our focus on translational medicine and partnerships with some of the world's leading academic institutions mean we are well positioned to advance the field of cutting edge therapeutics."

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About Silence Therapeutics plc

Silence Therapeutics is a leading RNA interference (RNAi) or 'gene silencing' platform technology company which has proprietary delivery systems. Combined, RNAi and delivery platforms enable the development of multiple products to multiple drug targets allowing the development of novel therapeutics for diseases with high unmet medical need.

Silence is one of only a handful of listed companies globally which has human validated RNA delivery technology. Its RNAi is one of the safest and most widely tested, with over 400 patients dosed and no immune response observed so far. Silence's RNAi has been used in three Phase 2 clinical trials, two of which are awaiting results. It also has a robust IP estate protecting its proprietary technology.