Establishing Research With Horizon Therapeutics' Robert Stoffel, Ph.D.

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One of the most challenging aspects of running a biopharmaceutical business is managing research and development . It's a high stakes game from which wins and losses spring forth , requiring a constant balancing act between immediate scientific curiosity and longer term business driving efficiency . I'm Matt Piller . This is the Business of Biotech .

Establishing an R&D function is exactly the topic of today's conversation , and I couldn't have found a better guest to help me suss it out . Dr Robert Stofill is VP of Research at Horizon Therapeutics , where , in 2021 , he was hired explicitly to develop the company's R&D strategy .

With 25 years of scientific leadership experience at ABV and Bristol Myers Swibb , to his credit , dr Stofill was a solid choice for the job and in just a couple of short years at Horizon , he's made good on the promise . I'm feeling fortunate and honored that Dr Stofill has agreed to spend some time with us . Dr Stofill , welcome to the show .

I truly do have a chemistry degree , but it's really more biological sciences that I study at that point .

So I want to start the conversation just getting some flavor for what it's like to be on the early-stage research team or lead the early-stage research team at a relatively large biopharma company . I get the sense , I guess , from the outside looking in . I just envision that as sort of like being in a constant startup environment .

So building in that research as well as that research connection to the later-stage portfolio , so that's been really kind of fun to come in there and to generate what that might look like .

So , even though it is biotech-y-like , there's a maturity there in the pipeline that really helps in terms of that the drive of how we do things and the way we think about things .

Two-part question like what did you have to work with coming in ? It's got to be a little bit daunting coming in and starting a new department and a new initiative in an established company . So what did you have to work with coming in ? And then where did the strategy begin ?

Then there was the way that Horizon looked at stuff was really to try to build out that mid-stage pipeline . So they acquired VLF Biosciences . So that was a spinoff from Menomune and that the research part of the research group came in from that , from that group and they're the ones that are responsible for DAX and DAZ and a Plissna in the pipeline .

So that group , through Menomune and VLF , made that science happen to push those forward . So they were part of the group .

So the group at that point moved up to about 15 to 17 in size and that's about the time that I joined and at that point we were working on okay , where do we want to operate , how do we want to grow and what you know , how do we want to do that ?

So we worked with McKenzie and other groups there to try to figure out , okay , how do we want to do this ? Because it you know , the company was very , very interested in moving forward in that direction . So they're building up a significant research group . So how do you do that ?

Do you keep acquiring , or do you actually more piecemeal and more specifically put in the things that you need ? So I think this gets to the point that that you were asking about before . On the biotech side , so we do a lot of outsourcing . So that still is a big component of what we do . But we've also built a lot of expertise in these areas .

So we have expertise in autoimmunity , we have expertise in gout , we have expertise in fibrosis , and that's the main core of the things that we go after ?

You're constantly talking and horizon is the size where you talk all the time . So we have a direct connection with the executive committee and we talk about the things that we're working on all the time and the things that are of interest , and you build your data set and you build the story that helps to compel the investment .

What else did you have to do in terms of sort of the infrastructure or the guardrails around the department , policies and procedures , even like what went into kind of creating the operating environment that you work in today ?

And the next one would really be determination and or , potentially , grit as a way to think about that , because the things we do are so difficult to get done and you have to have the determination to keep moving things forward and to push that rock up the hill , the boulder up the hill .

And then , finally , the most important thing and this is where I think the management piece comes in is really you want to be able to operate with no fear . You want to be able to do the things that you think are important to get things done , and that's one of the things I feel at Horizon really drives a lot of that .

And certainly the thing that I want to propagate within our group is no sense of fear , really , where you can have that curiosity and that determination and you can do the things that you need to do . So you think about that culturally .

That's the piece for me that really starts off , where you create that environment and I can tell you , like the group that we have here and then we have individuals that are at our field location and then also South Francisco .

It's a very happy group , it's interconnected and really everyone is trying to work with one another and that , for me , is the biggest thing .

So , as we grow and we push the numbers up in terms of the group , making sure that we keep that cohesiveness and the ability to create that environment where there's that curiosity , the termination and no fear in each and every scientist .

Can you give any sort of insight into what you're looking for ?

Now we're actually at a point where we have that maturity level and we're going into lower experience for people coming potentially right out of school , out of postdocs , to really kind of build up that next generation of researchers , essentially .

How did you , did you have to and , if so , how did you go about creating support beyond your own department ?

So then it was really more about building the connections and the bridges within the different functions within Horizon and really trying to connect and then to show the value of the team . And it really starts with not only the pipeline build that we're doing right now , but then also that connection within the organization .

And one of the one of the biggest things for us is that you know , when you think about where we are as a group , we can , we're doing things internally , like driving our own projects forward , but there's also a lot of external innovation that has to happen to build that pipeline up and to keep it going .

So we worked very closely with our business development groups in within Horizon and I would say you know the group you know at our peak was probably about 50% of the job of each individual was really looking at different opportunities .

So they would be , they would be scouting and things like that that would be happening outside of our group and then we would be the ones that would judge essentially the science and the merits of those of those projects . When it was really , it was a really nice connectivity within the organization that we had there .

And then as you get bigger as a group , you become more dependent on things like ordering becomes a bigger problem , all of those things . So you have to really think about how you're going to address those concerns as you move forward and get bigger as a group .

So then we had to ensure that we had the right infrastructure to move forward , and some things we got right and other things we didn't really , so we had to really kind of adjust as we went along . And then the other thing that is very important is making sure that we have enough lab space .

So currently , right now , we're a little bit tight , so we're expanding into space here . So there's lots of work ongoing in terms of the learnings that we have now applying to the new space that we're building out , as well as the new building that will come online in a few years .

So they were essentially the masters of CROs and driving things like that and to a large extent , that's a lot of still what we do , although we have a couple of partners with Alpine and Hemoshir that actually really helped to drive some of our portfolio forward .

So in essence , we're still doing a very similar type of job where we have what bench work that happens . So we have cell biology , that we do , but then as we start to move in vivo , all of that work becomes outsourced .

I know it's never that clean Like there was some to your point you just made . There was some R&D function happening there already . But tell us a little bit about that transition from coming on board , working out a strategy and then at what point you felt like we're really we've got a functioning , capable team of R&D professionals working towards a common goal .

And really , you think about this in research , you think about moving the needle so from like an exploratory project to a lead up project to then something that would then transition to R&D enabling studies , and we were moving that needle over the year and a half .

So that really , I think for me , those are the milestones that we were seeing and I'm like , ok , wow , we're able to do this , we're functioning and we're going . I don't think I've ever really switched out of that .

I mean , the strategy is still there , but the tactics that we're doing to try to get there and some of the tweaking is still is still part of what we do .

The thing that's exciting about that is that we've been able to deliver on the things that we've promised we would deliver on . So that's the thing that's been very , very nice over the past year or so to really see projects transitioning to different milestones .

So we have external innovation I mentioned that before but then we also have really nice connectivities with medical affairs , with the asset teams and the clinical side of things . So we really have excellent connections there .

So we're learning about things all the time and some of the some of the areas where we have really the best connectivity are on some of the market and drugs that we have and really where we're working with KOLs and we're trying to understand those biologies and those processes even more to lead to the next level of next generation of targets that we can bring

forward . The other component there that that is really strong for us is the academic collaborations . We have significant amount of academic collaborators that we work with , really helping us to understand disease biology as well as mechanistic notes that we are that we're interested in .

So having all of that together really helps us to drive the portfolio and think about where we go next .

There we have multiple collaborations that we're working on to try to understand mechanistically how the B cell is playing a role which can then inform against different disease states that you would go into .

So it is a B cell depleter , so it's CD 19 based and depletes a significant proportion of the different B cells , and one of the things that we've learned through testing , both preclinically and then in humans , is that that level of B cell depletion really leads to this , this fantastic efficacy that that you see in these disease states .

So the thing that we're trying to understand more about is like what are the specific B cell lineages and or effector functions that that are there , that that we're impacting , as well as the plasma blasts and the antibodies ? So we really , we really are very excited about that .

It's an area of keen interest for us as we , as we move forward in the next couple of years , and I can tell you there's a lot of interest externally as well too , because there's other B cell depleting modalities that are that are playing out potentially in the immune space .

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One of the things that that new and emerging biotechs struggle with is , you know , I guess , drawing a direct line , or trying to maintain a direct line , between research and and and business efficiency . Right , like product efficiency , development efficiency . What have you found are sort of some of the keys to research efficiency from a science standpoint ?

You know , making sure that the work that you're doing in the research function is going to carry on to an efficient business proposition further down the line .

And then I think the other piece of that is really trying to understand , like mechanistically , how it would work in a disease state . And if you look at our portfolio of marketed drugs , they have fantastic efficacy in gout , thyroid eye disease , and we just mentioned about the B cell and NMOSD . They're really phenomenal .

So there's no question about the efficacy that they have there , and that's really what we're trying to strive for is to get to that .

I think the other component there , too , that is a little bit more difficult to get to , and this is also part of the work that we try to do , and I'll just call this in general like more spatial biology , so really trying to understand mechanistically what's driving different populations of disease patients .

And this is , I think , an area that we're going into and that this is a lot different than when I started in terms of thinking about disease states and potentially different populations within a disease state that might respond differently to one therapeutic versus another therapeutic .

Is that sort of something that you guys pursue , and why is that good for the goal of moving , moving into clinic and eventually patients ?

So you might even think about okay , we'll test it here first , because we can get the answer that we want , saying that mechanistically it's working the way that it should , and then think about going into into a different indication . So I think that horizon has multiple approaches where there is , I would say , more platform opportunity like that .

But then also where we are more singular in things . So like we have the IGF mechanism that is playing out completely incredibly well in thyroid eye disease , in gout .

It's really one mechanistic node that's there , right , it's uric acid levels and we have we have Christexa , but then we also have other programs that we're working on earlier on in the pipeline where we're trying to manipulate uric acid as well .

So if you think about it like that , you can think that there's nodes within the disease that are very important and you want to go after those , and then how can you manipulate those nodes .

Or you can think about like what we have with our PDC mechanism , the CD40 mechanism , and also say like the B cell mechanism , where it could go into multiple disease areas , because that mechanism is potentially playing out there .

Excuse me , but I'm hoping you can sort of lay out , like for someone who is not familiar with the interaction of research with other departments in a biopharma company , what are the sort of some of the fundamental , I guess , other departments with which you interact and why ?

So we interact very , very well with those groups and really are making sure that we're aligned completely with those with that and the direction that we need to go into . But then beyond that , then you have the other R&D function , so you have the clinical side of things .

And then we also have another group called translational sciences , where you think about okay , we've got this idea that we want to have , we want to we move it through preclinical testing . But then we want to move into humans and figure out okay , how do we , how do we test that ? So what's the appropriate disease state to go into ?

And then we think about how we covered the target . And then are we getting the signal on the biomarker side that support moving into efficacy studies and or having efficacy coupled with that in parallel . And that's the . I think that's the , you know , the heart of the groups that we really try to work with to try to move things forward .

But obviously some of those , some of those interactions you just pointed out , are very key not just to advance of the science but advance of the business , right like making sure that the work that's going on early stages is pointing in the right direction .

So we kind of work hand in hand with those , with our clinical groups , to really try to talk through , okay , mechanistically , this is how we think this is operating and or we have questions to you , know to probe against that as well .

I don't know if this might be an impossible question to answer , because I'm sure it changes pretty , pretty drastically depending on what you're working on and what stage , but what's sort of the cadence of inbound inquisition that your department is subject to right , like , how many questions are you answering or attempting to answer at any given time ? So what ?

So I'm just wondering what that environment's like in terms of the cadence and volume of inbound inquisition that your department is subject to .

So we do this quite often where we have discussions about what's going on within the research portfolio and then we do updates I would say probably on a monthly basis or so of what things are .

Yep and those are like company-wide updates or for specific dates and they go out , they go out in written form or there's presentations that happen , and then if there's more explicit questions , we answer those as well .

Tell me a little bit about how those positions , the positions you held in those organizations , have informed what you're doing in your current research capacity .

So part of that infrastructure build at that point was really getting to high throughput screening and technology to try to support a whole target ID that was coming and things like that . So I was involved in that .

I was in a high throughput screening group and really at that point merging technology with biology and really learned a tremendous about how compounds behave , how they manipulate and then how we can use that to understand the pharmacology in an enzyme assay or in a cell .

But one of the things that happened to me when I was there during the support of that was that I was working on this project . It was a metabolic disease project and it was actually the regulation of parathyroid hormone and there's this receptor called the calcium-sense receptor and it actually can sense it .

So calcium in the body and the blood is 1.2 , I always say gigawatts but it's 1.2 millimolar and 10% in either direction changes the amount of PTH that's secreted , which then regulates how much calcium comes out of the bone .

So one of the things that was interesting to me as we were working on that was really getting to understand that biology even more and how it worked . So the way that it worked , we were figuring out , was that it actually sense the calcium and when it was at the right level it would actually oscillate at a certain pace .

So calcium inside the cell would then oscillate and you could see that fluorescently . So that was really very cool . And then as it went up or down , you either stop , this oscillation stopped or it went more rapidly and the cell sense that and then responded to it .

So when I started to understand that more , I'm like I feel like I'm pointing in the wrong direction . I'm pointing towards this technology piece and high throughput screening . But I think it's really this understanding of the biology that is really what interests me more and I think where the true bottleneck is to move forward .

So then that's when I went looking around for a different position within a therapeutic area and landed at ABDI in immunology and it turned out that Sandra Rufo , who was the site head at the MetaBall group that I was at at that point it was Hope Longa , jersey .

He transitioned up to ABDI to lead the research group there , site head at the Worcester site where I was at , and then eventually became the head of R&D and he actually had overlap with Tim Wolbert , which is also interesting , so it's not a trained Abbott guy as well .

So at that in there it was very exciting to me because there I got to really understand the biology and then how it related to the disease state and that has been like for me the thing that has driven me .

So , even though I've been like project lead for projects that have moved into the clinic , it was always that connectivity to the science , to the disease state and to the patient that really drove everything in the way that I think about things .

For me , it was a once in a lifetime opportunity to come into this group and it really starts right from the very top with our CEO , tim , that he's a patient himself , he says that all the time in public and he really cares about the patient experience and that drives so much of what we do at Horizon .

And it comes down to the other piece that I didn't know exactly about before I got here was how much the focus the company has on people in the company as well .

So there's the patients and then there's the employees and it creates this incredible environment that really leads to this drive and energy all the way from the top , all the way down the company , and we really feel that .

So it was a very unique opportunity to come in and to build out this research function that would then match what was happening on the clinical side , so the rest of R&D , and then also on the marketing side the clinical and reaching the patients .

So that it's been a very amazing experience being able to do that and to match that , and I can say that we've set out to try to get to a level where we would be putting two molecules per year into R&D enabling studies and we're really getting to that level . So it's been really , really amazing .

So it's a little bit more difficult to do that . But if you look at our mid-stage pipeline , you will see multiple indications , multiple disease states being tested out across the different therapies and that is it's a little bit on the unique side and one of the things that really excites me about Horizon knowing that what we produce we'll get tested in people .

So that's a very cool thing . But then if you look at that mid-stage pipeline and the research that went into that so we talked about the B-cell biology piece and how interesting that is there's also then on the autoimmunity side . We have research that has happened that has led to DAX and PDC depletion . We also have 1116 , which is PDC , and dendritic cells .

Those are really kind of cold mechanisms where we think that they're driving a lot of the disease biology , so that you think of them as kind of sitting in the tissue and orchestrating all around them and by removing them we think we're gonna have a pretty significant impact on the disease state , not only on the interferon part of that , but then also the other

extracurricular activity that those cells bring to the table . And then we also have , within that pipeline that , the CD40 , cd40 ligand mechanism . So that is really a pretty fantastic thing that we see and we actually have some very positive data that's come out in chokrins .

I'm sure that you've probably seen that , both in this patient one population which some other therapies come out and shown a little bit of activity there , but then really in this patient two population which has pretty significant impact on pain , dryness and fatigue , and we've had a really big impact there .

And that goes all the way back to the research focusing on the ligand side of that arm CD40 ligand versus CD40 , and really driving greater efficacy in that mechanism . So we're very excited about that . And then into the earlier part of things we're doing gout research .

I actually don't remember how much of this is public , so I'll be very careful here with the other things that we're working on , but we have a collaboration with Hemoshia where we're working on new gout targets . We actually have pretty significantly built out our fibrosis area , really thinking about how we've worked on so well with thyroid eye disease .

So we're working in areas there and then looking at those mechanisms that are coming up there . How else can we move them into different disease states ? And one of the things that's kind of fascinating to me is , as I came in , I did not really know much about thyroid eye disease . I had more experience with scleroderma and with pulmonary fibrosis .

If you look at the fat layer in scleroderma , it actually completely disappears . So that's part of what happens . You get this hardening of the skin , but the fat layer disappears . It's one of the first things that happen . If you look at thyroid eye disease , the fat actually expands behind the eye and you have some of the similar players there .

So you have fibroblast , you have immune cells and then you have stromal cells that are there , including the fibroblast , and mechanistically we definitely were just like what's going on here , why the difference is , even though the players are similar . What is driving that ?

So that's a keen area for us to try to understand that and we think that that can then play out in other disease states once we figure that out and figure out the targets that are involved there and then beyond that , the other bigger area for us is really autoimmunity and how that relates to rare diseases .

So we have our research where is being led by Jody Cornell , who is really they're really focused on looking at effector regulator imbalance and how do you actually manipulate that , and we have collaborations with Alpine Biosciences to help us drive some of that .

And then we also have other academic groups where we're working with in terms of trying to identify novel targets in different disease states that we think are gonna play out in that area as well .

So we'll be paying attention to that . I mean , it's exciting stuff and hopefully we'll be able to have Horizon back on the show a little bit down the road to talk about some of these research efforts coming to fruition in the clinic . What's next for you in the meantime , dr Stoffel ? Like I mean , obviously you're very happy in your role .

You guys are doing terrific work . Any aspirations for your time at Horizon , or I don't know just what your next steps might look like .

Check us out at bioprocessonlinecom , where you can subscribe to both the podcast and my newsletter at bioprocessonlinecom backslashbob . In the meantime , thanks for listening .