Silence Therapeutics Plc American Depository Share H.C. Wainwright 28th Annual Global Investment Conference

Yeah. Silence has been around for a while, about 20 years. Our focus is obviously small interfering RNA. We have a proprietary technology, like many other companies in the space. What's special is, like other companies, we have specific chemistry modifications that we apply to our sequences. We have a proprietary algorithm to choose what we believe are the most potent and specific sequences to target for silencing of gene products, disease-associated proteins. And we have also algorithms that ensure that we choose the safest compounds. So not only are they durable and specific, but they're safe, and we have always updating our algorithms there. We also have IP around our linkers, and of course we use GalNAc technology, which is specific to the hepatocyte center in the liver. That is very similar to the other companies, but the other pieces of it is really our proprietary technology.

Like I said, we've been in the space for a long time. We transitioned from really a research-focused company to a clinical stage company over the last 5 to 6 years with now 3 products that have entered the market, and I think that just underscores the safety and the confidence we have in our technology.

Well, it's the right way to manage polycythemia vera. Some of the other conditions may not necessarily be targeted with a suppression of TMPRSS6. But the patients with polycythemia, as you probably know, have a JAK mutation. That causes an increase in the number of RBCs, the red blood cells, so their hematocrit goes high. When you have a high hematocrit, you can have viscous blood essentially, and it sets you up for thromboembolic events. These could be as serious as cardiovascular death or, of course, thromboembolic events that are non-fatal as well as bleeds. We know that one of the major needs in patients with polycythemia vera is controlling the hematocrit and the red blood cell count. Our compound targets TMPRSS6. TMPRSS6 is a negative regulator of hepcidin production. Hepcidin is the major regulator of iron in the body.

By blocking TMPRSS6 in the hepatocytes, you take off the brake and you increase the amount of hepcidin that is available. Hepcidin will then restrict iron to the bone marrow and therefore essentially starve the bone marrow of the iron needed to continue to overproduce RBCs. That's really the technology. It's very elegant and rather simple, to be honest with you. Fits very nicely with the underlying pathophysiology.

Yeah. So maybe just a quick description of the trial. This was a continuation of a combined phase I, phase II protocol. We had reported our phase I results at ASH and then additional data at EHA last year and the year prior. We were very confident in what we were seeing there. We saw very robust effects, increase in hepcidin that was associated with a decrease in systemic iron availability and an ability to maintain hematocrit below 45%, which is really the target in these folks, while essentially eliminating the need for phlebotomy in well-controlled patients. The phase II study took one of those doses, the 6 mg per kg dose. We had weight-based dosing both in phase I and phase II. We looked at 3 mgs, 6 mgs, and 9 mgs.

We decided to take the 6 mgs forward into the phase II, but rather than give it in the Q6-week regimen that everyone got in phase I, we decided based on the results of phase I and the durability that we were seeing in our phase I patients, that we could actually evaluate a longer duration interval. We are looking at both Q6, which would essentially replicate and confirm one of the doses that we had and the results we had in phase I, but also look at a quarterly dosing schedule, which was Q12. As you mentioned, in the phase II study, we enrolled the same population of patients that we did in phase I.

All of these patients is what we refer to as phlebotomy-dependent, meaning regardless of whether they are high risk, low risk patients, by definition over 60 or with a history of thromboembolic events, or whether they were well controlled, well, actually they were all well controlled, but whether they were on background cytoreductive therapy or not, perhaps just on phlebotomy or phlebotomy plus additional treatments like hydroxyurea or JAKAFI, which is a JAK compound, or BESREMi, which is a pegylated interferon, all those patients were allowed into the trial. And what we demonstrated is we replicated the Q6-week arm of the phase I study, but we also demonstrated a very robust effect in the quarterly arm.