Harnessing a Natural Mechanism to Silence Disease

March 11, 2022

RNA interference offers the potential disrupt the translation of instructions from genes with mutations into proteins that drive diseases. Silence Therapeutics is developing a pipeline of therapies based on its mRNAi Gold platform that allows it to target short interfering RNAs to liver cells. We spoke to Mark Rothera, who at the time served as CEO of Silence Therapeutics and Giles Campion, Silence’s chief medical officer and head of R&D, about the company’s platform technology, why it can be used to target a broad range of genetic diseases, and the company’s programs in development. Since recording this podcast, Rothera stepped down as CEO and the company named Craig Tooman, who had served as CFO of the company since January 2021, as its new president and CEO.


Daniel Levine: Mark, Giles. Thanks for joining us.

Mark Rothera: Thanks for the invitation.

Daniel Levine: We’re going to talk about Silence Therapeutics, its siRNA platform technology, and its potential to treat a range of genetic diseases. Let’s start with siRNAs, or short interfering RNAs. What are they and how do they work?

Mark Rothera: Well, let me just start by painting a picture of the company, Silence. We’ve been around for 20 years and we focused on RNA interference—so the ability to knock down or silence the expression of disease causing proteins in the liver. And we do that with these short interfering RNA molecules. They’re designed specifically to target the gene in question at the mRNA level in liver cells. It’s something that we’ve developed enormous knowhow around over many, many years now, and we can target this at genetic disease, whether it’s rare or even nonrare.

Daniel Levine: What makes them compelling as a therapeutic approach?

Mark Rothera: I’ll start and maybe Giles will want to add some comments. This is a remarkable technology because I’ve worked in many different types of genetic medicine, but what we have here is the ability with just a few subcutaneous injections a year to be able to control a genetic condition by achieving a substantial reduction in the production of these disease causing proteins in the liver. So, it’s very precise in addressing those specific genes in question that we want to stop being expressed at the mRNA level, but very easy to take. You’re just talking about two to four injections a year, typically.

Giles Campion: And I think what’s interesting about the technology is that it harnesses a natural process in the body originally designed to try and control infections. And so, we’re able to take use of that and use it to reduce, as Mark said, the production of disease related proteins. The important thing about it is as a genetic therapy it has the advantage that [while] it has the specificity of genetic therapy, but unlike gene therapy, it is reversible. We’re not trying to introduce new DNA into the body. What we’re trying to do is to disrupt the message going from a disease-related gene to producing the protein. So, it has that amount of both specificity and reversibility.

Daniel Levine: There has long been excitement over the therapeutic potential of siRNAs, but it’s been difficult to fully realize the potential because of delivery challenges, their instability, and the duration of their effect. Silence has what it calls its RNAi Gold platform. What are you able to do with this platform and how does it address these challenges?

Giles Campion: You’re right. When this technology was initially developed, you have identified some of the problems. One is stabilization, making sure that the molecules hang around in the body long enough to do what they’re meant to do, and the other is delivery. What has been, I think, a breakthrough has been the ability to conjugate these molecules to a delivery moiety called GalNAc that gives specific delivery to the liver where there are a whole range of disease-related genes that we can target.

Daniel Levine: And you mentioned you could do this by dosing a patient just several times a year. What is the lasting effect of a treatment?

Giles Campion: Well, the way that this works is that once the molecules get into the cell, they’re initially in the endosome and then they’re released into the cytoplasm where they interact with a mechanism called RISC [RNA-induced silencing complex] and it’s RISC where these molecules are processed so that the appropriate strand then is delivered into the cytoplasm to down-regulate the messenger RNA or degrade the messenger RNA, and therefore interrupt the message. Now there is still some discussion about how the duration of action is actually maintained. It’s either because the process is catalytic—that means it continues—so one molecule can process a whole number of messenger RNAs, or that there is potentially some depot within the cell, but what it ends up with is that you only have to administer these molecules as little as twice a year.

Daniel Levine: The technology is used to target cells in the liver. What’s the range of conditions that you can treat by targeting the liver?

Mark Rothera: What is interesting is there are 14,000 genes expressed in the liver. You know, there are 30,000 in man, so 14,000 genes expressed in the liver is certainly a very large range of genes in question. And if you look at our sector today, those of us that are focused on RNA interference, there’s probably less than 140 programs targeting different genes expressed in the liver today. Today there’s probably less than 1 percent of expressed genes in the liver that are being addressed or trying to be addressed. So, our general thesis is we’re still at the infancy of this technology specifically associated with the liver- expressed genes. We think that there are years ahead of finding targets that are disease-causing in the liver and then looking to address those targets by specifically knocking them down using siRNA.

Daniel Levine: I want to talk about your pipeline, but before we do, talk to me about your partnering strategy and how this fits into your business model. You’ve announced deals with AstraZeneca, Mallinckrodt, and Takeda, and a total potential of 14 programs in your pipeline with up to $6 billion in potential milestones, plus royalties. How do you structure these deals and what is Silence’s role in the preclinical or clinical development of these candidates?

Mark Rothera: Yeah, great question. Well first, the whole of this begins by recognizing it’s taken us 20 years to develop what we think is a really exciting platform, the GalNAc platform, and there’s a lot of opportunity here. So, the way that we want to maximize that opportunity is partly through partnership and partly through developing our own pipeline. The partnership side is really important. As you say, AstraZeneca, Mallinckrodt, and also more recently Hansoh, just to update you, are three partners with actually a total of 16 programs now, and $7.5 billion in milestones and royalties. And the way these generally are set up is that the partner will contribute either partly or fully to the cost of the experiments that are being conducted preclinically. They will generally pay an upfront at the start of the partnership and they’ll pay milestones as we go through the various preclinical and then clinical development and finally commercialization phases. They will have an option typically at the end of phase 1 whether to take that in house and then go all the way themselves, but essentially through to phase 1, we are generally conduct the work necessary.

Daniel Levine: And do these agreements cover your costs? Are they structured to be profitable from the start?

Mark Rothera: Yeah, they generally more than cover the cost. Once you look at the fact that there’s an upfront payment and then there are milestone payments along the way and contributing payments for costs associated with the experiments that have been conducted. They generally more than wash their face. And then I think the big opportunity comes as you go further down the development pathway and you head towards regulatory approvals and commercialization. Then ultimately we have royalty streams that come from the sales from these programs.

Daniel Levine: How do you balance the demands and resources for these partnered programs versus your own pipeline?

Mark Rothera: Well, I think we’re quite strategic about the way we choose to partner. For example, with AstraZeneca, not only do we have a great company as a partner that I think we have a very good working relationship with, and we knew that from the time that we evaluated this as an option, but they also bring additional know-how and capabilities into the company because they’re actually interested not only in leveraging our GalNAc platform with liver-directed targets, but they’re also interested in looking at siRNA being delivered to other organ systems for diseases outside of the liver. So, if you like the additional know-how and capability, these are very important. And then if I take Hansoh as a more recent partnership, they’re a leading innovative Chinese company. We did a deal with them because the structure of that deal gave us access to the world’s second largest pharmaceutical marketplace. Also, the way this was structured is that two of the three targets are essentially going to be owned by Silence, but they will keep China rights, and then one of the targets they will have global rights. So, it really balanced our approach between partnering and going at alone.

Daniel Levine: And with regards to the pipeline of products you’re developing on your own, do you ultimately expect to partner those, or are you seeking to commercialize those on your own?

Mark Rothera: It’ll be a mix. And I think, perhaps Giles will want to comment on SLN360 in a minute, which is one of our two really lead programs where we’ve just had very exciting clinical data. At that one we’re more likely to partner just because of the scale of this, we’re talking about a cardiovascular indication addressing up to 20 percent of the world’s population, whereas SLN124 is for a range of hematological conditions where there’s unmet need for patients and where we think the scaling of this is something that a company our size could undertake all the way to market.

Daniel Levine: Let’s talk about your pipeline. You mentioned SLN360, which is in development for high lipoprotein. What is SLN360? How does it work?

Giles Campion: Well, as Mark indicated, we’ve been really excited by some results that we just released and it really exemplifies that what siRNA can do in terms of the power of the drug. We showed that giving this drug to patients with elevated LP(a) [lipoprotein A] reduced that risk factor by up to 98 percent with a decrease up to 81 percent persisting 150 days. So, you’ve got something that is really effective after a single dose and has a long duration of action and speaks very much to what Mark was saying in terms of being extremely patient friendly. Now, the target is a lipoprotein, which is to some extent being hidden beneath cholesterol because it shares some of the constituents of cholesterol. It’s only recently that it’s come into its own right as being recognized as a major risk factor. In fact, we now know that up to 20 percent of the world’s population have elevated levels of this risk factor. And if you have double the normal level, then that increases your risk of cardiovascular disease, including the heart to by two to three times. So, it’s significant. The other aspect about it is that it’s genetic. Unlike cholesterol, it’s not something that you can manage by lifestyle or by diet. This is something you are born with and at the moment, there’s no effective pharmacotherapy. So, there’s a huge unmet need there. In fact, given the prevalence, it is a major health policy issue, which we are hoping to be able to address with SLN360.

Daniel Levine: Novartis’s Leqvio was approved at the end of 2021. What does that mean for the development of SLN360? Are you going after the same patients?

Giles Campion: Well, it’s a different target. They were going after a target called PCSK9, which is really another way to approach LDL cholesterol. LPA a is a completely different target, and I think in terms of understanding cardiovascular risk, it’s one of the reasons why heart disease is still a major problem despite having effective therapies to try and reduce cholesterol. It’s because of other risk factors. So, it’s very important to be able to address this.

Daniel Levine: Would you be going after the same types of patients, or is it a different subset of patients?

Giles Campion: Well, as I said, there will be some overlap because if 20 percent of the population has elevated LP(a), some of those individuals are also going to have elevated cholesterol. So, it will be a mixed population. Especially if you’re going after patients with established cardiovascular disease, many of them will be on drugs designed to reduce cholesterol, such as statins.

Daniel Levine: You’re also in the clinic with SLN124, which is in development for beta thalassemia, myelodysplastic syndrome, and polycythemia vera. What is SLN124?

Giles Campion: Well, this is another siRNA, for a rare disease this time. It’s dealing with individuals that have so-called iron loading anemias, specifically beta thalassemia and MDS, and that’s where we are in patients right now. But as you indicated, because we’re dealing with a central mechanism it has a number of different applications. What it does is it controls levels of hepcidin, and hepcidin has been recognized as being the master regulator of iron flux in the body and has been compared to insulin—the way that insulin controls glucose. So hepcidin controls iron levels and iron levels play a fundamental part in terms of the severity of the anemia in these conditions.

Daniel Levine: And what’s known about that from studies that have been done today?

Giles Campion: Well, what’s so nice about this modality is that what we’ve seen is good reproducibility between the work we’ve done in animal models or preclinical species and what we’ve seen in humans. So what we’ve shown in preclinically is that if you administer SLN124 you get an increase in hepcidin and a reduction in serum iron, and then ultimately in these animals a robust improvement in hemoglobin, which is what you’re trying to do. These people are suffering from anemia and require often frequent transfusions. So, that’s what we saw preclinically. And then we reported a study in healthy volunteers last year, which showed after a single dose, the same sort of profile that we’ve seen with 124, a really nice effect in terms of increasing hepcidin, a long duration of action, and no clinically relevant safety issues.

Daniel Levine: What’s the development path forward for either of these?

Mark Rothera: I think for SLN360, which is a large cardiovascular indication, the next stage is a phase 2 study, which would be around 250 to 300 subjects with stable cardiovascular disease and elevated lipoprotein A. So, that’s some that we’re talking to the regulators about initiating in the second half of this year, and then maybe I’ll leave Giles to speak about the SLN124 program, which again, is series of rare hematological conditions that we’re looking to address.

Giles Campion: Yeah, what’s exciting about this is that if you’re dealing with a central mechanism, then generally there are a number of applications and we see that in anemia. So, by being able to regulate iron levels at the level of red cell formation in the bone marrow in these two diseases, beta thalassemia and myelodysplastic syndrome, [where] iron levels are too high so you want to reduce iron levels to improve the red cell formation. In other diseases such as polycythemia vera, this is essentially a red cell cancer where there’s uncontrolled proliferation of red cells. And of course, it’s one of the major resources that the bone marrow needs to make red cells. Iron is something, if you can control by controlling hepcidin, then you can reduce the proliferation. You can reduce the hematocrit and ultimately reduce some of the issues that these patients have such as a fourfold risk of a thrombotic disease. Then there are other areas that we are looking at—sickle cell disease, stem cell transplant, all of these are areas where iron regulation plays a critical role in the disease process and something we think we can control by SLN124.

Daniel Levine: Mark, through your career you’ve held executive positions at a number of companies focused on genetic diseases. Most recently, you were CEO at Orchard Therapeutics, before that you were at PTC Therapeutics, among others. What have you learned about developing and commercializing these therapies that’s coloring your approach at Silence?

Mark Rothera: Thank you for that question. I’ve been 20 years now working in the field of rare diseases, including actually working in cystic fibrosis in the late nineties and then Shire Human Genetic Therapies for about seven years as well. And I know it’s been said many, many times, but we are a lot closer to patient communities in what we do in developing a medicine for a rare disease. And I think that throughout our organization, throughout Giles’ as R&D organization, and other parts of our organization, there is a genuine spirit of that engagement to understand what the issues are to think about a patient perspective when it comes to trials, to think about information around what we are doing, thinking about partnership on trial recruitment, and ultimately of course—and I’ve been all the way through the spectrum from development through to bringing a medicine to market for rare diseases—I think that the patient voice later on in the journey as well in expressing the disease burden in understanding the impact of treatment and then helping with market access considerations is also extremely important, as well as the regulatory process, because by definition, when these are rare conditions, the amount of awareness around the condition and what is meaningful to adjust is never as good as want, so that connection with the patient community is extremely important to us.

Giles Campion: And I think if your listeners go onto our website, you’ll get an indication of that. We’ve been working quite closely with the patient communities and launched various initiatives to try and increase awareness of these diseases and to help the community. There’s something that we currently are running called “Color the City Rare,” which people might like to go on and have a look at as a sort of game to test their knowledge of rare disease. And then “Letter to My Younger Self,” which is a way that we’ve been asking patients who are in the adult phase, particularly with beta thalassemia to write to themselves as younger patients and just give themselves some hope that although they are feeling difficulties with their disease, there are ways through it, and actually people can achieve a lot despite having a rare genetic condition.

Daniel Levine: Mark Rothera, president and CEO of Silence Therapeutics, and Giles Campion, head of R&D and chief medical officer for Silence. Giles, Mark, thanks so much for your time today,

Mark Rothera: Thank you very much. Also much appreciated, been a pleasure.


This transcript has been edited for clarity and readability.

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