Silence Therapeutics Plc American Depository Share Morgan Stanley 24th Annual Global Healthcare Conference

Thank you, Mike. It's nice to be here. Just maybe just a few words on Silence. We are a global biopharmaceutical company, clinical stage, that focuses on the development of small interfering RNA compounds. We've been fortunate. We have what we refer to as our GOLD platform, which means GalNAc oligonucleotide delivery platform, and we target the liver using GalNAc as the ligand. But we have a range of technologies that we apply to our compounds and provides us with the IP. We have a very robust IP library, and that includes the sequences, the manner in which we choose our sequences, the chemistry modifications that we apply to our sequences to ensure that they're durable, potent and safe, as well as IP around the linkers that we use to attach our sequences to the GalNAc and direct it to the hepatocytes.

The bottom line is, we've been successful over the last few years. We've really transferred to being from a research company into a clinical stage company, and we've had three products in the market. Our lead compound now that we're really focused on, obviously, is divesiran.

Yeah, sure. Polycythemia vera is a rare myeloproliferative neoplasm. It is associated in almost all patients with a JAK2 mutation. It is a driver mutation, and it leads to an overproduction of red blood cells. You can also have an overproduction of other blood cell lines. The issue is that when you have an overproduction of RBCs, red blood cells, your hematocrit, which is the portion of your blood, the volume of your blood that is associated with the RBCs, it grows, and it causes viscosity of the blood, and that can induce thromboembolic events and other severe cardiovascular outcomes. In these patients, what you try to do is reduce the hematocrit and retain hematocrit below 45%, which is considered a more safe range for these patients.

There was a very nice study that was done back and published in The New England Journal of Medicine back in 2012 or so, 2013, that demonstrated that even if you maintain patients in the range of 46% to 50% versus under 45%, the former have four times elevation of cardiovascular death and cardiovascular events such as thromboembolism and bleeding. That is the target of treatment, maintaining these patients below 45%. Most of these patients are older patients, although we see patients as young as their 30s. About 85% of the patients are over 40, and a good portion of the patients present older than 60. We typically divide the population into high risk or low risk.

The high-risk population is based on being over 60, because that places you at a higher risk just based on age, or any age patient that also has had a history of a thromboembolism. We really aim our treatment at reducing the likelihood of having thromboembolisms or other cardiovascular events, and we do that by giving them phlebotomies, which is really the first-line treatment, which is simply removing blood from the patient with some regularity. That can work, but actually can complicate their symptomatic presentation and the burden of the symptoms, because these patients tend to be iron deficient, even at baseline, because their bone marrow is chewing up iron to create and make the RBCs, overproduce RBCs. You add to that by removing blood in order to help them, so you are complicating their iron deficient status and contributing to the symptom burden.

If we can do anything to reduce the need for phlebotomy, that would be tremendous. I just want to add one more point about that is only about 75%, 80%. No more than 25% or 30% of patients maintain their hematocrit below 45% on a regular basis. There is a huge issue here and a gap in treatment that we think divesiran may be able to serve.

Yeah, it's a good question. Bottom line is there are a number of other different therapies out there besides phlebotomy. We often use cytoreductive agents such as hydroxyurea. There are newer compounds like the pegylated interferons like BESREMi, or for instance, the JAK compounds, which are used second or third line, but they are available for patients as well. And then very recently, the first hepcidin-directed therapy, which is a mimetic, was approved, and I think that's very exciting. The opportunity for us is probably in the range of GBP 1 billion to GBP 2 billion for our compound. The space, I think, is going to be growing with the entry of a new class of medicines that is largely well tolerated, safe, but very effective.

What's really interesting, and I'll just reflect on this for a moment, is the label for rusfertide, which is the mimetic, actually has an indication that's quite broad.

It is for erythrocytosis, even though we all are studying patients that are phlebotomy dependent and meet certain criteria to get involved in the trials. The indication that was given to them is actually very encouraging because we think this is a great pathway to exploit for helping patients to manage their condition much better. I think that is a good indication of potential size of the market even expanding.