Silence Therapeutics Plc

Good morning and good afternoon, everyone. Thank you for joining us today. Joining me today on the call are Mark Rothra, our president and CEO, who will provide an update on the business, Dr. Giles Campion, our head of R&D and chief medical officer, who will provide an update on our clinical programs, and Craig Tooman, our chief financial officer, who will review our financials before opening the call to your questions. For those of you participating by a conference call, the accompanying slides can be accessed by going to the Investors section of our corporate website, at www.silence-therapeutics.com. Turning to slide two, I'd like to remind you that during today's call, management will make projections for other forward-looking statements regarding anticipated future events or the future financial performance of the company, including clinical development timing and objectives, the therapeutic potential of our product candidates, our operational plans and strategies, anticipated milestone payments, anticipated operating and capital expenditures, business prospects, and projected cash runway. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to Mark. Mark?

Thanks, Jen. Good afternoon and good morning, everyone. Thank you for joining us today. Now let's move to slide three. In January, I set out our path to value creation. We must maximize the substantial opportunity of our proprietary mRNAi goal platform to target disease-associated genes in the liver rapidly and effectively. We are doing this through a combination of building and advancing our proprietary pipeline as well as our partner pipeline. We call this the hybrid model. We made strong progress advancing both areas in the first half of the year and are on track to significantly expand our portfolio of gold platform programs by delivering two to three INDs per year from 2023. Moving to slide four. Starting with our proprietary pipeline, we achieved a historic milestone in May when we reported the first clinical data from our gold platform. The SLM124 Healthy Volunteer Study demonstrated the potential of our technology and showed that we can successfully translate the results from preclinical models into humans. In addition to this, we started dosing patients in two wholly owned phase one programs, the SLN360 Apollo program for cardiovascular disease due to high levels of lipoprotein A, or LpA, and the SLN124 Gemini 2 program for thalassemia and myodysplastic syndrome, or MDS. We also advanced our partnered pipeline. We started work on a second undisclosed target with AstraZeneca, and are on track to initiate work on a total of five targets within the first three years of our collaboration for cardiovascular, renal, metabolic, and respiratory diseases. Under our Malincroft collaboration for complement-mediated diseases, we started work on the third and final target of the partnership agreement and initiated IND-enabling studies for the Complement Pathway C3 Targeting Program. The first half of the year highlighted the value of leveraging a hybrid business model. In addition to completing a financing led by top US healthcare funds, we received a substantial amount of non-diluted capital from our collaboration partners. As a result of our hybrid model and getting money in from both sources, we ended June with a strong cash position. Craig will review our financials in more detail later on in the call. With positive clinical data from our goal platform, we believe it has become more apparent how powerful the GALNAC approach may be to developing new precision medicines. Partnership interest remains strong. We are well positioned today, both from a financial and platform perspective, to further advance our clinical pipeline and deliver on our IND goal. Moving to slide five. What is particularly attractive about our goal platform and the GalNec siRNA approach is it is a well-established modality with a track record of clinical success. In fact, historically, GalNec siRNA programs have had a high success rate in moving through the clinic from phase one to phase three compared to the pharma industry average. This means that the return on discovery investment for these programs has the potential to be much better than is typical for our industry. That's why we are committed to cranking up the engine on our discovery pipeline, as well as advancing our clinical pipeline. Moving to slide six, I'd like to focus on upcoming events and anticipated milestones. Starting with SLN360, our lead clinical stage proprietary program for cardiovascular disease due to high LP little a. This morning, we announced the good news that we have fully enrolled four cohorts of the SLN360 single ascending dose study, despite the challenges associated with COVID-19. We anticipate reporting top line data from the four cohorts in the first quarter of 2022. The protocol includes the option to add a fifth cohort if we want to learn more about the clinical profile of SLN360. We remain well positioned to start the phase two study in the second half of next year, subject to regulatory discussions. Moving to our second clinical stage, proprietary program, SLN124 for Thalassemia and MDS. We plan to present additional results from the SLN124 Healthy Volunteer Study at ASH in December pending abstract acceptance. Giles will review the positive top line data we presented from the SLN124 Healthy Volunteer Study in May in just a moment. But first, I want to update you on our timeline for the SLN124 phase one program in people living with thalassemia and MDS. While we have been successful in implementing a number of mitigation strategies to minimize the impact of COVID on our clinical programs, the SLN124 program is more complex. Thalassemia and MDS are both rare diseases prevalent in areas hardest hit by COVID-19. We selected multiple sites across Asia, Middle East, and Europe where thalassemia and MDS are most prevalent. However, some key sites have not been activated yet due to COVID-19 surges. We are uncertain today how the situation will evolve and therefore need to be more conservative with our timeline. We are now guiding that both of the SLN124 single ascending dose studies in thalassemia and MBS will read out in the summer of 2022. We will add further sites as a contingency and continue to work closely with local patient advocacy organizations to inform and educate patients about the trials to expedite the process. Beyond our evaluation of SLN124 for thalassemia and MDS, the healthy volunteer study showed the potential of SLN124 to become a franchise that is much broader than these two indications through its ability to control the production of hepcidin, a key regulator of iron balance in the body. We announced this morning that we will host an R&D day in New York on the 21st of October and look forward to discussing the SLN124 and SLN360 programs as well as our broader pipeline in more detail then. With that, I'll turn the call over to Giles for a clinical update. Giles?

Thanks, Mark. Moving to slide seven. As Mark mentioned, we announced today that we have completed enrollment in four cohorts. of the SLN360 single ascending dose study in healthy volunteers with high LP little a. This is a global, randomized, double-blind, placebo-controlled study assessing individuals with high LP little a levels at or above 60 milligrams per deciliter. Remember, 50 milligrams per deciliter is the threshold at which cardiovascular experts agree that we should look to treat patients. A level above this significantly increases the risk for a serious cardiovascular event. In the SLN360 single ascending dose study, we'll be looking at safety, LP little a reduction from baseline, and durability of effect over the follow-up period, which is around five months. I often get asked what success looks like for this study. Moving to slide eight, we want to replicate the excellent profile shown here in the non-human primate model. This demonstrated robust LP little a knockdown of around 90% with effects lasting for at least two months, which was the duration of the study. In addition, preclinical safety studies have shown an excellent safety profile, which is key, particularly when you're considering a potential preventative treatment for around 20% of the world's population. For the SLN360 single ascending dose study, clinicians generally consider around 70 to 80 percent reduction clinically relevant. We are optimistic, based on preclinical data and the GalNac conjugated SRNA modality, that we will have a long duration of action lasting at least a few months, potentially longer. Moving to slide nine and the SLM124 program for phthalosemine MBS. These are both characterized by a relative deficiency of hepcidin, which is the central regulator of iron distribution in the body. SLN124 is a galnet-conjugated siRNA targeting TMPRSS6, a gene that limits the production of hepcidin in the liver. Here we are looking at data from a rodent model for thalassemia, but by controlling hepcidin production, we believe SLN124 can address a range of hematological conditions, as Mark indicated earlier. In this model, you can see that SLN124 reduces temperature to six, raised hepcidin levels, and in turn, lowered iron levels, and improved red cell production as measured by a robust increase in hemoglobin by up to two point grams per deciliter. In the ongoing SLN124 patient studies, anything greater than a gram is considered clinically meaningful. Moving to slide 10. In May, we announced positive top-line data from the SLN124 Healthy Volunteer Study that exceeded our expectations. This study demonstrated both the excellent safety profile of sRNA and truth of mechanism. All doses of SLN124 were safe and well-tolerated with no serious or treatment-emergent adverse events. Following a single dose, SLN124 increased average hepcidin up to an approximate four-fold and reduced CRMI by around 50%. These effects were sustained throughout the eight-week study, indicating a long duration of action. On slide 11, you can see SLN124 increased hepcidin at each dose level, and that effect was sustained throughout the study. You can see on slide 12 that SLN124 meaningfully reduced serum ion levels after a single dose, and that effect was also maintained throughout the study. Importantly, this study was conducted in healthy individuals with a normal ion metabolism, and we anticipate seeing even greater impact in patients with hep C deficiency. Moving to slide 13. Here's an overview of the two single ascending dose studies we are running with SLN124. one in thalassemia and one in NBS patients. We are enrolling 56 patients in each study and have up to four cohorts per study. Given the positive data from the Gemini study and how consistent these data are with our preclinical models, we're feeling very optimistic about the potential for SLN124 in thalassemia and NBS. And as we've mentioned, we believe that by controlling the production of hepcidin, SLN124 can address a range of hematological conditions. We presented data at the European Hematological Association Congress in June that highlighted the potential for using this approach to treat polycythemia rivera. This is another indication we're exploring, and we look forward to discussing more at our upcoming R&D day in October. With that, I'll turn the call over to Craig to review our financials.