Developing Therapy Delivery Options For Autoimmune And Allergic Diseases At Revolo Biotherapeutics

In this episode of In Combination, host Tom von Gunden combines the perspectives of three executives at Revolo Biotherapeutics – CEO Woody Bryan, Chief Scientific Officer Roly Foulkes, and Chief Medical Officer Kari Brown – in a discussion about developing and delivering peptide-based alternatives to steroids for allergic and autoimmune diseases. Targeting conditions such as eosinophilic esophagitis (EoE) and atopic dermatitis, the Revolo team describes how the company works to advance multiple administration routes for restoring immune homeostasis. These options for patients include infusion (IV), subcutaneous, and sublingual.

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of In Combination, the series in which we hear from folks with differing perspectives based on the roles that they're in within a biopharma [industry] organization. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for the series. Today I am joined by three folks from Revolo Biotherapeutics, a company which is working in the space of treating allergic and other autoimmune conditions.

And for today's conversation “in combination,” coming from Revolo Bio is CEO Woody Bryan.

Welcome, Woody.

Woody, Bryan, CEO, Revolo Biotherapeutics:

Thanks, Tom. Great to be here.

Well, it's my pleasure to have you here.

Also joining me is Chief Scientific Officer Roly Foulkes.

Welcome, Roly.

Roly Foulkes, Chief Scientific Officer, Revolo Biotherapeutics:

Thanks, Tom. Looking forward to the discussion.

Thank you for being here.

And we’re also joined by Chief Medical Officer Kari Brown.

Welcome, Kari.

Kari Brown, Chief Medical Officer, Revolo Biotherapeutics:

Thanks, Tom. Glad I can be a part.

Well, good to have all of you here. So, [let’s start with] just a little bit of background, just so that the folks in the audience know what we're eventually going to be focusing on in more detail. And that is going to be what's in your pipeline, [including] a candidate called 1104 that you're working on a couple of different routes of administration for — [one] subcutaneous and one sublingual — to help folks treat allergic and other autoimmune conditions. So, we'll get into more of the detail on that, momentarily.

But before we do, I think it would be really interesting for our “in combination” conversation — since you all have different executive titles and functional areas that you oversee — to tell us a little bit about your background. What do you know or have experienced or have passion around [regarding] allergic and autoimmune diseases and [the] formulations and delivery mechanisms for those? So, a little bit of that background tracing to put your perspective in context.

Let's start with you, Roly.

Foulkes:  I spent 25 years of my career at UCB pharma when it was formerly known as Celltech. They were one of the big developers at the time and still are, really, in developing novel therapies for treating autoimmune and allergic disease.

My frustration was that these types of approaches were targeting single pathway, single cytokines, with lots of benefit for the patients —but you just could not get all the patients into remission, and you couldn't keep them in there. So, I was always interested in developing or working with novel approaches, which got around that problem.

I came across Revolo about seven years ago, and I started working with them and became the chief scientific officer. And the big difference here, compared to my experience in the past, is we have therapies which induce tolerance of the immune system. So, rather than being a big blockbuster —inhibiting pathways for long periods of time — our approach to restore what we call immune homeostasis. And that has the potential to treat more and more patients and keep them in remission.

Great. Well, thank you for giving us a little background and some flavor of how you arrived in the seat you’re in there.

Woody, let's move to you next as the chief executive officer. What brought you there? Trace that a little bit for us.

Bryan: Sure. Tom. So, my background educationally is in pharmaceutics; I have a PhD in pharmaceutics. I started in the industry doing drug delivery work at Schering-Plough, obviously a large, fully integrated pharmaceutical company. So, you'll hear a lot of my comments today that come from the excitement, among a number of things, from the standpoint of drug delivery. And what it means to the patient population has been very intriguing to me and been a part of my background.

So, I started out doing drug development early in my career and then transitioned into more corporate development, business development, [and] executive management roles. I've been fortunate to be a part of building out several existing businesses. Was at Shire for a while, part of the team that spun a division out of Shire to start Supernus, which is today a commercial stage, Nasdaq-traded CNS [central nervous system] company. And then on to Lupin to do similar [work[ and then Sucampo.

So, one of my passions and what really brought me to Revolo is the ability to be part of a smaller team that not only innovates but sets strategy and has to implement it. The novel approach we're taking to treating autoimmune and allergic diseases: If you look at what's going on in the space, there is a real need and a recognition [that] there needs to be a new generation, mechanistically, to bring more treatment options to patients. These are areas where prevalence is growing rapidly; the unmet need continues to grow. Although there are some new therapies in the market, they aren’t the end-all, be-all. And then you bring into the equation, if you will, our 1104 program and also our 1805 possess attributes that lend themselves to being delivered by different routes of administration.

Kari, do you want to tell us a little bit about what brings you to the position there [at Revolo] and how that informs your perspective on the work there? A little bit about the background trajectory for you?

Brown: Yes, great. Thanks, Tom.

So, I come to this with training as an allergist, immunologist, physician. And I'll say that the space is — as you hear from Woody and others — really needing innovation. That innovation, I think, over the past few years has really started to have begun. But I will say that standards of care in allergic disease still include steroids, which can be very effective drugs but carry some safety concerns and have been drugs for decades and decades. So, what's exciting for me is the perspective of innovation in the space, and particularly, as you've mentioned with Revelo, really looking at broader mechanisms that can work across multiple diseases.

It’s clear when you hear from patients with atopic diseases that they want options. There are, depending on the disease, some options for treatment. But there are many patients whose  needs still are not met.

Gotcha. Thanks for that. Let's stick with the theme of the patient with the first substantive question I’m going to ask you. And that is — especially for those in our audience, like me, who don't actually, thankfully, suffer from allergic or autoimmune conditions in any kind of chronic way: What has the experience typically been like? You have all alluded to the need to create a different scenario for those [patients], but can you describe some of the common conditions under that umbrella and what someone would do as a patient or what a clinician would help them to try to do, historically?

Brown: Yes, right. So, I think that, in both the autoimmune space and in the atopic or allergic disease space, it’s the immune system that's involved, right? So, what you're trying to do is dampen the immune system. Ideally, you're dampening the portion that's causing the disease. Obviously, steroids are something that [operates as] a kind of blunt force object, but they can work. But that's where we're trying to move to a more tailored approach to decrease the inflammation that's happening from the disease.

So, there’s a broad spectrum between allergic and atopic versus autoimmune diseases in which patients are experiencing how it impacts their life. But you can probably say, across the spectrum, [that] these are diseases that can impact someone every day. And some pretty significant impact on quality of life is out there. Research has been done on probably all of the diseases in these spaces that the quality of life can be significantly decreased. And particularly if I focus on some of the diseases that we're looking at in EoE [eosinophilic esophagitis] or atopic dermatitis.

So, for EOE, just recently, approved drugs have come onto the market. But still, standard of care can include steroids. This is a disease where individuals have an allergic reaction in their esophagus. So, you can imagine that eating becomes quite an issue for them. And obviously our lives can be focused around food. So, it can be quite a challenging disease that these individuals have [with] painful swallowing and difficulty eating. So that is something that really impacts their quality of life. And if disease goes on for prolonged periods of time, they can actually have narrowing of their esophagus and have impaction of food there. So, that's something that's really challenging for those patients.

In atopic dermatitis, it’s really, obviously, more visual; you can see that disease on the skin. But the irritation around itching and the lack of sleep that patients can have with it is really where you hear more about the challenges that people have with this disease. And so, patients are really looking for treatments that can help control the visual aspect of the disease, the itching, but also [offer] convenient treatments. Topical steroids have been a mainstay of treatment, which can work. Some patients … they don't work for. But [there is[ also the challenge of applying these treatments, topically and consistently; they can become a challenge. So, moving more into drugs that could be injected or oral, which the space has moved into. But there are still patients [for whom] their needs are not met with these options.

Gotcha. So, let's go ahead and move, then, to the science of what you're working on there. So, to address these needs, I'm interested, obviously, in hearing about anything around the formulation decisions, [the] formulation challenges, as well as, obviously, what we mentioned before from a delivery perspective. And that is the options of subcutaneous or sublingual.

So, I don't know, Woody or Roly, if you want to take us …

Bryan: Maybe we can share a little bit about mechanistically what we're doing and what it means. And then I can add what we're doing from a delivery standpoint —decisions around that and how they complement one another. Roly?

Foulkes: Thanks, Woody. So, following on from what Kari was just saying: The diseases that we are working on in — allergy and autoimmune diseases — happen because of inappropriate activation over our immune system or a dysregulation of our immune system, which results in something called a loss of tolerance. And that's really important because these individuals then are mounting an inappropriate immune response to an allergen or certain parts of their body in autoimmune disease.

As I said before, our [the industry’s] approach over the last number of decades has been to target some of the very downstream cells or downstream chemical mediators that cause the disease — with varying amounts of success. But the big thing is that you suppress key pathways for long periods of time. And even by doing that, you can't get the majority of patients into remission. If they're in remission, they can come out of remission quite easily. And there are clear safety implications of blocking key pathways for long periods of time.

So, our approach, really, is to try and understand what it is in the immune system, which cells are important in the immune system, that signal to tell us to have this dysregulation. And we call that acting upstream. And we've been lucky to work with a drug called 1104, which, in its nature has been shown to be what we call a tolerogenic protein, which means it can modify the immune system. And we know from papers that have been published that this particular protein is able to prevent people from getting allergy, particularly atopic dermatitis and allergy.

And the big breakthrough for us was understanding that. We then made drugs based on that protein, and 1104 is one of those drugs. It's a peptide. And it's able to moderate the immune system in a way that reduces the problems associated with allergy. It's a very novel drug. It has a very, very short exposure time unlike some of the monoclonal antibodies, for example, that have a long half-life and exposure time of weeks.

Actually, 1104 has an exposure time of only about 20 minutes, but it's able to induce these long-term pharmacodynamics and efficacy because it's able to mount a response to our immune system that regulates the immune system. It's called the regulatory immune system, and it involves the production of activated,  what are called T regulatory cells [Tregs] and B regulatory cells [Bregs]. And this is really important because T regs and B regs are there precisely to stop out-of-control immune responses, which is what you have in allergy.

And so, building on that mechanism of action is all about a lot of other things that it also does. It's able to bring more broad biology to patients than what you can get from targeting single cytokines. And then I guess the other important thing is, unlike these other drugs that suppress, almost by 100%, pathways for long periods of time, what 1104 does is just regulate the immune system back to where it was. So, if anything has been raised or lowered, [it] just brings it back to where it was, which gives us a real advantage in terms of the safety considerations of 1104.

Great. Great detail.

Woody, I think you wanted to pick up with the delivery options.

Bryan: Yes. To add to our enthusiasm for mechanistically what we're bringing to the table in this rationale around broader biology impact, we talk a lot about two arms of the immune response: You have the effector side, which is the inflammatory, the infiltration of whatever the cell type is —eosinophils, neutrophils, CD4s, CD8s —that are brought about into certain parts of the body based on introduction into an allergen, and they're out of control.

So, these downstream approaches that are out there impact certain subsets of those cell types, but it's not a broad-based approach. What they don't do is also have an impact on the regulatory side, which is the Treg, Breg side, which is a natural mechanism for controlling inflammatory response that the body is equipped with. We actually have an impact on the other side. So, we have this dual impact on effector and regulatory arms of the equation. We could go on all day about that.

But I think the other component is, if you start looking at individual indications: You asked earlier, why did we venture into EoE? Well, there have been a number of downstream single cytokine modalities that have been trialed in EOE, mainly because they said, oh, we know that our mechanism leads to a very impactful reduction of eosinophils. And they did; they did in EoE trials. But what they failed to have that do is to have that translate into clinical symptom improvement, which is a patient-reported outcome [PRO] in the form of DSQ [Dysphagia Symptom Questionnaire].  

So, it has become obvious from a number of failed trials in the space that there's a need for broader biology. And guess what? That's what we're doing.

If you then dive into what is available today in the market, you have steroids, as Kari mentioned. [They have] been used off-label for many years, and they are effective short-term. But every physician you talk to, they're trying to figure a way to not use them long-term because of their safety concerns. And we're back to, we need safer, effective, more convenient alternatives.

And that's where the drug delivery piece comes in. 1104 is unique in that, if you look at it, we've demonstrated it can be delivered IV, subcutaneously, and now, oral sublingually. These larger — like monoclonals — just because of the chemistry, are not a potential for oral delivery. And even subq [subcutaneous]: Roly mentioned the short pharmacokinetic profile of 20 minutes, but multiple weeks of pharmacodynamic effect after a single administration.

So, we're leading with our subq, and our data suggest we can probably dose —even if we dose weekly —but we think it's very probable we'll get there every two weeks and possibly even less frequent. [With] our combination of safety, efficacy, and ease of administration with the patient population that is amenable to subcutaneous, there's a tremendous lineup, if you will, of differentiators. And then eventually bringing sublingual into that space could even take it to another level.

If you move over to atopic derm, you have a [market offering] mix again of oral steroids [and] topical steroids that are relegated to those people that only have a body surface area of about less than 20% that's being affected by disease because no one wants to cover their entire body multiple times a day with a topical. And then you have the safety aspects there.

And then you have the monoclonals that are injected. And the JAKs [janus kinase inhibitors]; the JAKs have great safety concerns. They are also oral. The monoclonals, that I mentioned earlier, are dosed every few weeks, but they have their limitations.

So, there's a lot of room for innovation around subq there. Again, efficacious, safe. And then of course, sublingual would be highly competitive in that space, as well.

Of the various oral administration methods, can you say a little bit more about sublingual specifically for oral administration rather than other ways to get something into someone's body through the mouth and that passageway?

Bryan: So, you have traditional orally ingested, where you swallow a tablet or a capsule, right? 1104 is a peptide, so it's not typically amenable to ingestion because you have the acidic environment and enzymatic environment in the GI tract.

So, delivering it under the tongue, sublingually, is something that avoids the harsh environment of the stomach, as a first pass. Ironically —and I'll have Roly and Kari expand on this: Because of the cell types — mechanistically, 1104 has preference for MTA macrophages, what have you — delivering sublingually allows you a very efficient introduction to the lymphatic system and those avenues within the body where the cell types that 1104 interacts with to invoke its pharmacological effect reside and are trafficked, if you will. So, that route of delivery for 1104 — and subcutaneously — makes sense from a number of perspectives.

Roly, Kari, anything you want to add to that piece of it?

Foulkes: Yes, I can add to that a little bit. Often you deliver drugs into the blood because either your target is there or you need to move the drug around until it reaches the target. What we know about 1104 is that the target cells are in the blood, but the main cells of interest are not in the blood. As Woody says, they are in areas what we call lymphoid areas. So, the spleen and lymph nodes, where all of the immune cells all need to come together to interact with each other in a controlled way. And quite interestingly, by giving it subcutaneously and sublingually as Woody says, you get better access to these lymphoid areas.

And we've done some studies in preclinical models of allergic disease where we've shown almost equal efficacy of 1104 given either intravenously, subcutaneously, or sublingually at the same input dose, which is remarkable. And that will almost certainly work in our favor as we get further down developing subcutaneous and sublingual as viable options for 1104.

Great. One of the reasons I was happy to have all three of you join for this In Combination episode was, given even your titles and the hats that you wear implied by that — Chief Executive Officer, Chief Scientific Officer, and Chief Medical officer — [that it] would be very interesting if you could illuminate or illustrate something of what that means for each of you,  functionally and operationally, within the company.

What's your day-to-day like within the seat you sit in? Where do you overlap with each other? And then the teams that you oversee: How does collaboration and communication and interaction work to get everything you've described that's in motion happening?

Foulkes: Okay, should I start?

Any one of you.

Foulkes: OK, so what may not be obvious to the audience is that I'm based in London, and I have a small team in London, and the rest of the company is based in the US, mainly on the East Coast. And it's my job to be in charge of science, not only the work that we do with 1104 but also be well aware of what everybody else is doing: What's in the literature around novel mechanisms of action? How does that impact what we understand for 1104?

And I'm very lucky, actually, because I'm able to do that because we have a small team based around London. There's five of us. And they are very talented and experienced individuals. I've got an emeritus reader in immunology from Guy's Hospital. I have a professor of immunology from Exeter University. And I have two proven drug discovery experts.

And so, the five of us get together every Tuesday and every Wednesday. We have an office in London, and we travel in because we come from various angles and distances from London. And that's great because it's complete face-to-face time for two days. And that allows us to look at new data that are coming in around 1104, be aware of what’s going on externally, etc. And we're able to have all of those in-depth discussions and water cooler discussions that we all used to have, if we can remember, many, many years ago. So that's great.

What do we do? We don't have our own laboratories. And so, my view is that we need to have access to all of the key technologies that help us understand how 1104 works. And we do that by setting up e-collaborations with external laboratories. And we don't do that on a project-by-project or technology-by-technology basis. We strike up long-term collaborations where we can access FTEs that are related just to doing Revolo work. And they are essentially both our laboratories — because we have access to various different technologies when and where we want — and they essentially become part of the Revolo project team and get the interaction that way.

And so, that's proven to be a very important way we look at our science. And, obviously, I am the link mainly between what goes on in the UK and what goes on Woody’s department and Kari’s department as well. We have — I'm sure Woody and Kari can fill you in — we have lots and lots of discussions, transatlantic, on a very regular basis.

Brown: Just to add to that, I think part of it, too, is the size of Revolo. So, while we utilize consultants and external help. We have a pretty lean, mean, small type of team. And what that forces you to do is, there's no way to be in a silo doing what you're doing. You have to lean on other individuals. So, I think that we have a culture here that people want to lean on other individuals and share information. Because they want to say, well, what do you think about this? Let me share. This is where I'm going. What do you think? And I think that helps people maybe put down some defenses that could be there in terms of people inputting on something that's maybe not their expertise.

So, I think that's been really key in opening up conversations is that people wanting and willing to have discussion because there's also the culture that people are open to hearing feedback and also open to say, you know, I see that viewpoint. But actually because of this thing, we can't quite do it that way. And people really seem to, to understand that.

So, I think the culture has been set up in a way that allows us to have that discourse. And I also think that none of us take ourselves too seriously in terms of holding any of our views too precious so that someone couldn't challenge them, which I think is really key as well.

Great, great.

Woody, I'm sure you have something to add to this picture.

Bryan: You know, one of the main reasons I'm here is that I love the dynamic nature of what we do. In my role, just like everyone else, I wear a lot of hats. And I tell everyone, no two days, no two hours, are the same.

And I think having a small team, where we can have these candid discussions with very few, if any, preconceived notions and make strategic decisions, is very refreshing. One of the advantages of being very virtual in our operation is that we don't we don't have a platform or a preconceived notion around how we do things. We can have a discussion around what's best for the program. What are we trying to learn? What do we need to do to move the asset forward? And we can do it in quite an unbiased manner.

And like I said earlier, I've had the fortunate opportunity to be part of a couple of building exercises in the industry. And when you start something, you're part of starting something from scratch. And you put the team together, and you see the tough discussions, interpreting the data, and setting strategy and implementing. And then it turns into something that is really value-added and brings something just very interesting to the patient population. There's nothing more rewarding than everybody looking around, well, we were all part of that.

Kari mentioned we're so lean no one could have ever, if they wanted to, mail it in. We need everybody doing things and moving the ball forward and contributing, not just in their area of expertise. We’re all-hands-on-deck, and I love that. And I think people appreciate it.

You know, the environment is not for everyone. But I do believe certain personality types like the opportunity to do things and experience things and be part of things that aren't necessarily in their formal remit or expertise. They get a chance to see the bigger part of the business. They get a chance to learn about another aspect of the business. And it's invigorating, I think, to be able to contribute that way.

And also, we don't have to wait two weeks to have a discussion about something. We have a meeting coming up later. And we’ve actually tacked on a totally unrelated agenda item to the back of the meeting for something else just because a question was raised this morning that we need to discuss. That flexibility is refreshing.

Oh, sure. Yes, it sounds like it. I'll let you get back to the work of the company soon, but I will give each of you the opportunity to weigh in — you can if you'd like, if you have some perspective … I always like to end by asking or inviting you to comment on [this]:

If the work proceeds with the impact and effectiveness that you believe that it will, how do you envision what the lives and health of patients will be like in a future state once these things are in their midst for treatment options?

Brown: So, I can start there. I think, ideally it’s really the story around patients having options because we like to think about things very clearly in terms of, if we impact this pathway, it clears up the disease for patients. But the reality is [that] things are way more complex. And each patient is different.

So, I think it's key that we have options out there, particularly for different patients to choose, but also for one individual to, over time, have different options to control their disease. And so, I think that, as we move along and therapies like 1104 come to the market, it plugs right into that. It gives patients completely a different class of drugs, potentially different administration, if it's sublingually — a way to control their disease —and gives them that power to choose how they want to control their disease.

Great.

Roly, Woody? Any final words from either of you?

Foulkes: Yes. As I said right at the beginning, one of my frustrations working in pharma and biotech for all those years was the narrow-mindedness and [people] wanting to work on targets that have [been] thought to be proven. And you end up working on — everybody, every company, is working on — the same targets.

With our approach, because we started from understanding the biology around 1104 and its ability to return immune homeostasis, we are working on novel targets that nobody else is working. And that gives me a great thrill.

And, as you say, if we get to the point where these drugs get to the market, I believe that it gives us an opportunity to get more and more patients into remission than we've ever been able to do with the more traditional approaches.

That's great. Woody?

Bryan: Listen, just to oversimplify: When I look at these markets, in this day of real innovation  in the industry, and I look at what percentage of patients are still taking steroids: This industry has been trying to run away from steroids for a whole lifetime. And there has been some advancement. And so, there are obviously certain subsets of the patient population that have other options, but the number is still quite low. And it just doesn't take a rocket scientist to figure out that there is just massive unmet need around the existing patient populations for better efficacy, better safety, and dosage forms that they are more amenable to administering and being compliant with.

I think the other thing — Roly touched on this earlier — is [that] immunology is not a single switch solution, right? It's a multifaceted problem to solve. And we're bringing something that is, I like to look at it as sort of a feather across multiple switches in the cascade, not a hammer.

And it makes me nervous to see any of these therapies that crush something to zero, because if you're crushing something that exists naturally to zero, you’ve got to remind yourself that it was there at some level for a good reason, to begin with. And there's just a lot of evidence that these narrower approaches have their place, but they're not being broadly successful.

And so, what we're doing is an alternative to that. And again, we're excited about the safety elements. The efficacy was seen early on, but the safety piece has really, really been encouraging. And that gives us a lot of optionality going forward.

Well, great. It all sounds extremely promising. I love the target on patient needs out there, obviously.

So, Woody and Roly and Kari, I want to thank you for joining me for today's conversation to share the work that's going on there at Revolo Biotherapeutics and also how you work together to get that work done.

And I want to thank our audience for joining us, joining me, for another episode of In Combination. And we'll see you next time.