Silence Therapeutics plc Q2 FY2021 earnings call

• Mark mentioned the path to value creation through maximizing the proprietary mRNAi GOLD platform, advanced both proprietary and partnered pipelines, with progress in clinical data, own programs in clinic, and partnered programs. - Giles updated on SLN360: fully enrolled four cohorts of single ascending dose study, anticipate topline data in third quarter of 2022, and may add fifth cohort; on SLN124: plan to present additional results at ASH in December, but timelines adjusted due to COVID - 19, now guiding single ascending dose studies to read out in summer 2022, and highlighted potential of SLN124 beyond thalassemia and MDS. - Craig reviewed financials: revenue build from partnership programs, R&D and G&A costs increase, strong cash position with £81.2 million at end of June 2021, cash can fund through at least end of 2022 or early 2023.

For the six - month period ending June 30, 2021, the company recorded £5.8 million in revenues versus £1.1 million in the same period of 2020, largely from partnership programs with Mallinckrodt and AstraZeneca. R&D expenses were £15.6 million for the first six months of 2021 compared to £10.2 million in the first half of 2020. General administrative costs were approximately £9.1 million for the six months ending June 30, 2021 versus £5.2 million for the same period in 2020. The company's net loss for the six months ended June 30, 2021 was £20 million versus £11 million for the same period in 2020. At the end of June 2021, the company's cash, cash - equivalents and deposits were £81.2 million, including net proceeds from a financing and receipt from AstraZeneca.

• SLN360: anticipate reporting topline data from four cohorts in third quarter of 2022, remain well positioned to start Phase 2 study in second half of 2022 subject to regulatory discussions. - SLN124: both single ascending dose studies in thalassemia and MDS will read out in summer of 2022. - Cash position: believe cash should allow to fund the company through at least the end of 2022 or early 2023 without additional non - dilutive financing.

• COVID - 19 impact on clinical programs: the SLN124 program is more complex, with some key sites not activated yet due to COVID - 19 surges, and situation evolution is uncertain.

Q: Good morning, congrats on all the progress. I had a question about the 124 program and how we should think about haemoglobin, do you think it's the median change that matters or some sort of responder analysis or is the key read out kind of periods off transfusion? And then a second question on the second program, I understand you're treating LP(a) greater than 60, where things start to matter, will the FDA allow you to go up with the patients where LP(a) is very high, or do you have to start sort of around, 60?

A: Tom, thanks for the question. So, one on haemoglobin, the other one on LP(a), I think Giles, you are probably in the best position to answer these questions. Giles: Yes, I mean, as you are aware, if we start with the first one, as you are aware, the haemoglobinopathies represent a spectrum of disease from non - transfusion dependent to transfusion dependent. From a regulatory perspective, the way forward has been looking in reduction in transfusion dependency. So, for example, this dataset showed a -- look to the 30% reduction in transfusion frequency, so that would likely be the registration endpoint. In terms of, haemoglobin, that would be more relevant for the non - transfusion dependent population and there typically whether you, and I think this has been shown in both beta - thalassemia and also MDS, you are looking for about a 1 gm to 1.5 gm increase, which has been shown to be both clinically relevant and associated with increase in quality of life. So, I think that would be, those will be my thoughts in that regard. As far as LP(a) is concerned, I mean in our trial what we have is, an entry criterion having a level of at least 60 mg/dL, that doesn't mean that we are restricted in terms of upward values and indeed there are some individuals with quite high levels that have been included in that study. So, it will give us an opportunity to look at the effect on both those with minimally raised and also those with quite high levels.

Q: Thanks, hi good morning and good afternoon. I guess the first one is just a followup on SLN360. So, I'm wondering if you can give us an idea of what the clinical development plan for 360 could look like going forward, assuming a positive outcome in the Phase 1 program, and your views on eventually partnering this program? And then just on the SLN124, I'm just wondering if you can discuss some of the advantages of 124 as compared to some of the other modalities in development in these indications and including the ASR [ph] that targets TMPRSS6 and some of the other approaches in the field, such as with antibodies or gene therapies?

A: Mark: Thank you, Patrick. So let me start and I'll also ask Giles to comment. Yes, I think what we underlined today is that we're on track to initiate a Phase 2 for the SLN360 program in the second half of next year. And so, that is subject of course to discussions with the regulator, that with a single ascending dose data now expected in Q1, we think that gives us ample opportunity to initiate that Phase 2 study. What we’re thinking of as far as partnering is concerned is the important thing here is to do what's right for this brand, if you like. This is a blockbuster potential asset. It's going to be competing in a statin like market, which as you know is a massive market, is very similar in size and so what's important is to make sure that when it comes to scaling up and being ready to compete globally, that we have a great partner in place for that journey. So we'll be mindful about that as we think about the development program and when it makes most sense to bring on board a partner. I don’t know Giles, if you want to add anything on the development plan? Giles: Well, the comment I'll make is, one obviously, that's something that we’re intensively looking at, at the moment, both internally and with experts. And two, I think the path to some extent has been indicated by a traditional path of being indicated by our competitors, mainly Novartis, who are in the process of doing a cardiovascular outcome study. Obviously, the ability to show reducing LP(a) does correspond with the reduction of heart [ph] endpoints is going to be very important for the field. Amgen, who are also developing an siRNA, are currently doing a Phase 2 in those in subjects with atherosclerotic cardiovascular disease. So, I mean that is one way that obviously we are carefully looking to see what would make more sense for us. Mark: Well, that's a big question. Giles, do you want to take that one? Giles: I mean the, my first answer is, I'm really impressed by the profile of siRNA. And as we've shown in the healthy volunteer study that is characterized by a very strong target knockdown, a long duration of action, and a very good safety profile. And I think that has shown itself amongst the approved products or about to be approved products just around similar sort of profile there. So, I think that's the power of this modality in terms of looking at different therapeutic classes. If you look at the other compounds that are being developed in this field, I feel that the siRNA, really is a technology upgrade on antisense oligonucleotides. Why do I say that? Because one, the duration of action appears to be significantly longer and you can see that again in the LP(a) program where Novartis is dosing monthly. I think the evidence that we've seen, both from Amgen and hopefully from our own programs will be that dosing will be significantly of longer duration than our selves. And I think the other aspect is the safety aspect, the very clean social safety profile so far of siRNA I think compares very favorably. The other approaches in this area have been through hepcidin mimetic, so the same sort of pathway. The issue with hepcidin mimetics is they tend to have short durations of action. And when you're dealing with trying to control iron at the level of the [indiscernible], then you need to have very stable levels and iron overshoot is something you want to avoid and I think that's the issue with hepcidin mimetics. Again, to get the duration of action doses have to be increased, which are associated with an increase in adverse events. I think what they have done is that they have shown potentially very interesting alternative indication, so [indiscernible] for example, is showing some quite interesting results in post [indiscernible], and as Mark indicated, that's something else that we look at. So I think the strong effects of the siRNA together with the essential mechanism that hepcidin gives us in terms of iron regulation, we feel that this is a very attractive area for drug development.

Q: Hi, thanks everyone for taking the questions. First one is just on perhaps the APOLLO study, what are the guiding factors? I guess that you are thinking about initiating actually the cohort of dosing? And you've committed to top line guide in the first half of 2022 for the first four cohorts, so would we find out that answer after that guide or is this something you might be thinking about implementing before that? And then the other thing that I wanted to know is, now that at least you internally know the exact dosing of what you've used in the [indiscernible], where would a fifth cohort fit relative to the no adverse effect level you saw in [indiscernible]? And then for the new additional thoughts that I think, I might mention that you might need to add to try and simulate enrollment here. You know what sort of the -- how are you ensuring that those sites are as quality as the ones you initially picked and sort of what's the right revenue sets for getting them up and running? And then when you can start talking more about the AstraZeneca and the Takeda programs. I know you get that question a lot, but I just want to know in terms of like the legalities of it, like when you can come in versus that it is this solely in the hands of AstraZeneca and Takeda as to when they want to disclose those sort of targets moving forward?

A: Mark: Myles, thanks for the questions, I'll start and then hand over to Giles. But just to clarify, we've only made a very modest adjustment to the timing of the data. So we're talking about Q1 of 2022, just to be very clear on that front and that's with regard to the four cohorts of data from the APOLLO study, the first four cohorts. So as to decision making around the fifth cohort, I don't know if you'd like to add some comment around that Giles. Giles: Yes, I think the important thing about single ascending dose is that it really provides the data set that launches into further development. So what we've done in that protocol is to retain some flexibility so that if we need to then we can do an additional cohort. At this point in time, we don't anticipate it, but until we see the data we won't know for sure. And you know what you're trying to do is; one to maximize effects, so level of knockdown; two duration, which is clearly going to be important, particularly when you're dealing in a preventative indication and of course, safety. So that's what we do when we look at the results of different cohorts to make sure we've got the best combination of those factors to enable us to go forward, so hence the flexibility in the protocol to be able to do that. Mark: So in a moment I'll ask Giles to come in about the sites that are opened all right. I think the general point here is, with these being rare conditions, and obviously as we pointed out today, given that the prevalence of this condition includes numerous countries and Middle East for example and Asia, which have been more impacted by COVID - 19, we continue to build out our footprint for this study. So we've already identified 23 sites that we have in mind for the study, but we'll continue to add to those sites in areas that have been less impacted by COVID. So we're sort of balancing between areas of higher prevalence where potentially there's higher risk, but also other areas where there's perhaps lower risk with a perhaps slightly lower prevalence. And so it's a balancing act that we're doing globally here. But just to underline, we have a large number of sites that have been selected for this study. Giles: Yes. I mean, the idea is, as Mark indicated is we want to go to areas where the disease prevalence. clinicaltrials.gov doesn't accurately represent the extent of the facts we're looking at. We're looking at about 22, 23 sites around the Mediterranean literal and the Far East. And the reason for the delay is once we typically enter sites, once we got regulatory approval and there's also some administrative delay. So the rate of site activation is in fact greater. So that's our approach. Mark: Yes, great questions. Look, on the AstraZeneca collaboration, we are bound to be good partners, to be thoughtful about how much we communicate relative to highly competitive areas that they're very interested in. You know, but what is great is that we are progressing very well in the collaboration. We have already initiated work on two targets, and the goal is to have initiated on five targets within the first three years of this collaboration and remember that it's up to ten targets in total. I mean, one of the metrics you will see at the time of the collaboration progression, of course will be, milestone payment. And we have been open about the therapeutic areas that we’re working in, with them. So, to that extent, we're being open about the sort of therapeutic area categories. On the Takeda front, I think we had that exploratory deal in place, that you are very well aware of, and for one particular target, we've actually completed the work, that we were responsible for by the end of June, on the Technology Evaluation Agreement for that target. You know, Takeda now is evaluating that data, they have an option if they want to, to an exclusive follow - on license under the agreement, and they will be evaluating this alongside multiple approaches that they’re taking to address this particular target. So, I guess, it's a wait and see, as far as that is concerned.