Silence Therapeutics Plc American Depository Share Study result

Thank you, Heidi, and thanks everyone for joining us. With me today are Iain Ross, our Chairman and Interim Principal Executive Officer, who will provide some opening comments, and Steven Romano, our Chief R&D Officer, who will review the SANRECO study and top-line results. We will then open the call to your questions. Rhonda Hellums, our Chief Financial Officer, is also joining us on the line and available for questions. Today's press release and presentation are available on our corporate website at silence-therapeutics.com/events. Before we begin, I would like to remind you that this call will contain remarks concerning Silence's future expectations, clinical development plans and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995.

Factors that could cause these results to differ materially are described in today's press release, as well as our filings with the SEC. Any forward-looking statements that we make on this call are based on assumptions as of today, and we undertake no obligation to update these statements as a result of new information or future events. With that, I'd like to turn the call over to Iain.

Iain? Thank you, Gem, and good morning and good afternoon, everyone.

Earlier this morning, we issued a press release announcing positive top-line results for our Phase II SANRECO trial evaluating divesiran, a first-in-class siRNA therapy in patients with polycythemia vera or PV. Let me be clear, this is the big win scenario. We are absolutely thrilled with these results and what they could mean for patients, physicians, families, and the broader PV community. This is also an important milestone for Silence. Turning to slide four, Silence is a platform company that has pioneered siRNA research for over two decades. The PV results we are sharing today highlight the key strengths of the siRNA approach, high potency, durable effect, specificity, favorable tolerability, and the potential for infrequent dosing.

We now have completed clinical data across multiple programs in hundreds of patients with rare and cardiometabolic diseases, reinforcing the strength and productivity of our GOLD platform. We see a significant franchise opportunity for divesiran, our first-in-class siRNA therapy for PV, a rare hematologic disease with substantial unmet need. Of the roughly 150,000 patients in the U.S. and an estimated 3.5 million globally, most still rely on regular phlebotomy. Based on its emerging profile, we believe divesiran could offer a differentiated, best-in-class treatment option for PV patients. Beyond PV, encouraging preclinical data in several other hematologic conditions support the potential for divesiran to become a broader hematology franchise asset. Slide five. This shows why PV is our first indication and why it represents a compelling commercial opportunity. First, the unmet need remains significant. Many patients still rely on phlebotomy, underscoring inadequate durable disease control and a large addressable market.

Today's treatments have meaningful limitations. Physicians continue to navigate trade-offs in efficacy, safety, and tolerability, and the treatment burden. At the same time, Jakavi's approximately GBP 1 billion in annual PV sales demonstrates the strong commercial potential. We believe divesiran has the potential to raise the bar with a differentiated profile that combines the robust efficacy results, favorable safety profile, infrequent dosing, and an improved patient experience. Overall, we see a large underserved population, a validated market, and an opportunity for a best-in-class therapy with significant long-term value. Turning to slide six. Today, I'm very pleased to say the SANRECO top-line results delivered on all fronts. Let me repeat that. It delivered on all fronts. The study met its primary endpoint with strong response rates observed at both the every six-week and every 12-week dosing intervals. Divesiran was well-tolerated with no major safety concerns.

The results Steve is about to walk you through clearly support infrequent dosing and a potentially best-in-class product for the treatment of PV. With that, I will turn the call over to Steve to discuss the SANRECO program and the divesiran PV data in greater detail.

Steve? Thank you, Iain. We're very excited to share the top-line results of our SANRECO phase II trial.

Let's jump right in. As a reminder, PV is a rare myeloproliferative neoplasm. It's associated with a JAK mutation in nearly all patients and leads to a clonal expansion of red blood cells. This presents in patients as elevations in hematocrit levels. The primary objective of treatment is to reduce hematocrit and maintain it less than 45%. This is most often achieved through periodic therapeutic phlebotomy, the removal of blood from the patient. Today, we will be reporting on the SANRECO phase II results in 48 patients. As a reminder, we previously conducted a healthy volunteer study in 24 patients, and of course, the phase I portion of the ongoing SANRECO study in 21 patients. You're likely very familiar with the terrific results reported from that portion of the trial.

This slide highlights the global phase II trial locations. We conducted the trial in nine countries across four continents, the U.S., Europe, Southeast Asia, and Australia. The phase II trial has three components. The first is a 36-week double-blind randomized portion leading to the primary outcomes we will discuss shortly. The second component is a blinded extension period where those patients randomized to placebo in the previous period have been blindly randomized in a one-to-one fashion to six mg per kg, either Q6 weeks or Q12 weeks. All other patients remained on their initially randomized dose interval. The plan is to transition all patients to the dose interval chosen for phase III and follow patients out to 144 weeks for further safety and efficacy evaluation. I'd like to briefly go over a bit more detail on the phase II design prior to delivering the top-line results.

All patients met the World Health Organization criteria for PV and were considered phlebotomy-naïve. This was defined as having a minimum of three phlebotomies in the previous six months or five in the previous year. This is very similar to other trials ongoing in this condition. We allowed patients to be maintained on other standard of care cytoreductive treatment if their regimens were stable for a minimum of 12 weeks. Importantly, all patients entered with hematocrit well controlled, meaning less than 45%. Patients were randomized to drug or placebo in a one-to-one-to-one manner, with all patients receiving divesiran six mg per kg, but either on a Q6 or Q12 week interval. The primary endpoint was the proportion of patients maintaining hematocrit less than 45% without the need for phlebotomy during weeks 18 to 36. There were a number of secondary outcomes, which included safety, tolerability, PK, and quality-of-life measures.

Now we can turn to the results, which are quite exciting. As you can see, 88% of divesiran-treated patients met the criteria for response, versus 18% of those patients on placebo. This gives us a nearly 70% placebo-adjusted difference between divesiran and placebo. We were delighted to see this robust effect that we knew based on our phase I results that we had a potent compound. This was very highly significant with a p-value of less than 0.0001. Remember that the study was a phase II in an orphan condition, so the power was actually based on the combined arms, active arms, versus placebo. I just reviewed that data. We can also, of course, evaluate the effect of each active dose arm.

Here we see, once again, a very robust effect in both the Q12 week and the Q6 week arm, with response rates over 80% and 90% in the respective arms. These can essentially be considered similarly large response rates, over 60% and 70% placebo-adjusted differences. We will plan to move forward into phase III with the less frequent quarterly dosed interval. You may recall that the SANRECO trial was designed as a combined phase I, II trial, and that patients from phase I were eligible to enroll in phase II. Our assumption was that the timeframe between completion of the phase I trial, which was 16 weeks beyond a patient's last dose, and the initiation of phase II, would greatly minimize any potential carryover effects of earlier treatment exposure.