Silence Therapeutics Plc American Depository Share 12th Annual Cantor Fitzgerald Global Healthcare Conference

Thank you for having us.

Sure. Yeah. Silence is an siRNA company. We have been developing our technology for over 20 years. In the last seven to eight years, we have been focused primarily in the liver, so working on the GalNAc, and therefore we call it our mRNAi GOLD™ platform. In the last, I would say five to six years, we have been able to pull three of our programs forward into clinical development. Our lead asset, which is divesiran, just completed phase II, and Steve will, I am sure, walk through all the results from that phase II blinded placebo-controlled study, which was great. We also have a program that is phase III-ready, zerlasiran in cardiovascular. We did have a phase I that just completed ANGPTL3, that also had data results this year. We are focused right now primarily moving this divesiran program forward into phase III as quick as possible.

I think we will walk through those results, and you will see. We just raised $200 million, so that allows us to advance this program quickly.

Yeah. We are an siRNA technology, so we have proprietary algorithms that help us choose the right sequences, so that is critical obviously. We want to choose sequences that are both potent and durable. Then we have a range of chemistries, what we refer to as our toolbox, that we apply in different and unique ways. Every company has a similar range of chemistries that they apply to their compounds, but you can do that in many different ways, and this underscores our very robust IP positioning is our chemistries. We also obviously have proprietary linkers, and then the manner in which our linkers are connected to GalNAc is also part of our proprietary portfolio, IP-wise.

Yeah. Our lead indication is polycythemia vera. Polycythemia vera is associated with an overproduction of RBCs, also some other blood cell lineages, but elevations of hematocrit lead to greater viscosity of the blood. That leads to the risk of cardiovascular outcomes. That can be as severe, obviously, as fatal outcomes, but also bleeds and thromboembolic events. The challenges in PV and managing PV is that many patients cannot manage their hematocrits, even if they're aggressively managed with phlebotomies and even cytoreductive agents that are added as well, depending on the individual case requirements, cannot manage their hematocrits in a steady way, convincingly and durably keeping their hematocrit below 45. We know there's a 4-fold increase in cardiovascular death and thromboembolic events, even in patients who are maintained between 46 and 50.

There's a great need in PV patients, particularly those that are phlebotomy-dependent, to enhance or improve their ability to maintain hematocrits below 45. We target TMPRSS6. TMPRSS6 is a negative regulator of hepcidin. Hepcidin is the body's major modulator of iron. Blocking TMPRSS6 actually will increase the production of hepcidin. Increase in hepcidin will lead to restriction of iron to the bone marrow. Essentially, you're starving the bone marrow of the iron needed to continue to churn out RBCs. That's really how it works, and we have demonstrated that it works very robustly. This pathway has already been sort of precedented because you just have a new product. It's a different type of product than ours, but it's a hepcidin mimetic that's been approved, and so the pathway has been de-risked completely.

It's just a matter of us moving now forward into phase III and completing a confirmatory trial. Our phase II results were terrific.