Ultragenyx Pharmaceutical Inc. (RARE) Earnings Call Transcript & Summary

Hello, everyone. I'm Edwin Zhang a biotech analyst here at H.C. Wainwright. Welcome to our 2022 BioConnect Conference. It's my great pleasure to introduce Dr. Emil Kakkis, President and CEO of Ultragenyx. Welcome, Emil. Thanks for joining us.

Thanks for having me, Edwin.

Maybe first, Emil, could you give us a quick overview about the company and then we will dive into the clinical programs.

Sure. Ultragenyx is a rare disease company now entering our 12th year since founding. And we have, in that time, gone to 4 approvals for 3 products and are global rare disease company. We have 6 programs in the clinic, including 4 programs entering pivotal studies this year. So we're very busy, both from a pipeline and commercial standpoint. In addition, we have some recent news about an additional product collaboration with Regeneron for Evkeeza and a second product option for an FOP drug that's coming, which will help build out our commercial activities ex U.S. With that and the Angelman data update, which is showing that we are so far so good with our Angelman program, we're in a great position for 2022 to hit a number of execution time lines, data time lines and commercial time lines and execution results that I think will put us toward the top tier of rare disease companies now.

Excellent. Let's talk about setrusumab and osteogenesis imperfecta. I know some investors may still have questions on this program. Hopefully, we can sort it out a little bit. So tell us about this OI opportunity, the synergy with Crysvita franchise.

We looked at a number of genetic bone diseases after our success with Crysvita. We were looking at building on that franchise and our insights there. And the feeling was that there would be other antibodies that would have profound effect on bone. When looking at osteogenesis imperfecta, we found that most of our doctors, 90%, that treated XLH also treated OI and had usually more patients with OI than XLH. So it's a really substantial opportunity. In looking at OI more deeply, there's a lot of different modes that people proposed, but the effect of setrusumab on the Wnt signaling pathway by binding -- basically binding the protein that will regulate the recruitment of [ solid ] osteoblasts into bone-forming cells and stimulates bone anabolism is a very optimal type of mechanism when you're dealing with bone that is fractured and underproduced. In OI, we use the bones as being weak because they have defects in collagen. But in fact, the bigger problem is that the defect of collagen results in enhanced turnover of their bone as they're trying to fix the problem. And we think that an anabolic agent like setrusumab dealing with an anti-sclerostin mechanism in the Wnt signal pathway will drive recruitment of more osteoblasts into the sites of the bone that are weak, producing more bone, and in animal models, can restore bone strength to normal within weeks. And we believe in the human data that Mereo produced on setrusumab in human OI, showed improvements, for example, in lumbar bone density that are double what was seen with other anabolic agents. So we think that's proof of concept that setrusumab can dramatically improve bone mineral density in OI patients and gives us great confidence that this is a mechanism that's really an optimal one for treating OI.

Wonderful. Can you talk about the Phase II/III trial design? I know you have a Phase II part that's mainly for dose finding and safety -- yes. Is it on target yet?

Very close. Sites are up and we're very close. We expect to start enroll imminently and should be able to enroll promptly because there's a lot of patients out there. So the design of the study was based on the prior work that Mereo had done showing that between 2, 8 and 20, 20 was clearly the more potent dose. So we feel like 20 is a very potent dose that gave you the anabolic effect that I just talked about, right, double the mineral density in the lumbar spine. So what we're trying to do in the study here is optimize dose to is it 20 or do you need to go hire when you're now dealing with pediatric subjects, right? So their study was in adults. And in pediatrics, they tend to turn over or metabolize the antibodies faster. And for example, in XLH, Crysvita is dosed 1.6-fold higher in peds than in adults. So what we're doing in the Phase II part is now we're treating a lot of children 5 and up, and we want to look at dose of 20 or 40 to try to determine whether we should be going on the higher end for the younger patients to help develop a dose paradigm. So we achieved the same efficacy we saw but in all different ages. And so that gives us a better handle to optimize and tune the dose. Instead of doing a Phase III with 20 alone, by doing this, we'll make sure to get the optimal efficacy in those younger kids where the efficacy could be the most profound for their lives. So the first period we'll test them with 20 or 40 in a randomized design or placebo. We'll look at what we're seeing in the first couple of months with regard to biomarkers of anabolic collagen production, which is P1NP and other things. And we'll make an assessment there of what the dosing paradigm should be at different ages and then set that paradigm in place for the rest of Phase III, which will be a randomized controlled trial probably around a couple of hundred patients in the randomized trial. And while bone mineral density is an important measurement, we are focused on fractures as the primary endpoint. For the study, we are enrolling patients that have a higher fracture frequency, at least a couple of fractures within the last period, year to 2-year period. And we want to try to enroll as many patients with higher fracture as possible, who have the highest unmet need, right, who would be most likely adopters and also ones who would generate adequate power. We found that there's a pretty good fraction of those patients, and it will include both type 1s, type 3s and type 4 type patients with osteogenesis imperfecta.

So as you are trying to have a higher fracture grade patient, does it mean that you want to enroll more type 3 and 4 patients?

Well, it probably will give us more type 3s and 4s, but there are some type 1s that do have a lot of fractures too. But we -- I just would believe, Edwin, just in general for all rare disease products, you want to treat the sick people, right? That's kind of one of our what I call rare pearls of the company. You want to treat sick people. It's not only for the trial power, it's because those are the people that are going to adopt, the ones that are really having a lot of events. And I'm not concerned about a restriction to that. I'm not worried about that. I'm worried about treating people that have a problem that really need some treatment. And the trial will include people both naive or a bit on bisphosphonates, they're not going to be on bisphosphonates in the trial. But bisphosphonates, which are commonly used off-label in the studies that have been done have only shown maybe a 20% reduction in fracture. So it's not a big effect. So there's a lot of room for improvement, Edwin. But if you're going to run a trial, you certainly want to reach for higher-fracture patients. And that's kind of the approach we're taking. And it's the same approach we always do in our rare disease programs.

For the primary endpoint, are you only considered fractures on long bone or any bone fractures you will count?

It's -- the primary endpoint is any fracture that's clinically noted, like a notable that they have symptoms from. So it has to be clinically symptomatic fractures. It can be anywhere, and they seem to be documented by X-ray. So if you document by x-ray they have symptoms of a fracture, they do the X-ray, they got a fracture then that would count. We are going to look at asymptomatic fractures in enrolls, too. This is particularly a problem in the lumbar spine where it's harder to localize fractures. But if they do have fractured lumbar spine, and they clinically feel it, right, and we do an x-ray, then that would count. So it's clinically apparent fractures.

Looks like Amgen has OI trials with Prolia and romo. Should we worry about the potential competition?

Well, Amgen, they're a little company. Why worry about them. We're strong. The truth is we're smart and nimble but more importantly, we're focused on OI. OI for them is a requirement based on their patient -- the pediatric investigational plan that was approved in Europe. So as part of Evenity's approval, they have to get -- do the study. That was what was required of them by the EMA. So that's why they're doing it. But their label focuses on a 12-month-only treatment, right? That's what they're doing. They're not doing continuous treatment. They're not optimizing for OI. They're not changing the dose or optimizing. We're going to optimize for OI both the dose regimen and the maintenance regimen and long-term chronic therapy and they won't have that. So our view is that we'll be more highly focused on that population. Could -- the question usually comes to, well, if Evenity is out there, and it's an anti-sclerostin, why not use it off-label. How will that affect your pricing? Well, it could have some effect because this is a pretty large market population. So I think the pricing, even if we're moderated as we are at with -- for Crysvita, it wouldn't be as big a differential as people think. And since the dosing would be optimized, I really don't think it's going to be a big problem. We'll have to keep our eye on it. But -- and I do think EVENITY works as an anti-sclerostin, it works. So we'll have to look at that and just manage that in our commercial risk, but I do believe there are so many patients. And I also believe that chronic treatment, not 12 months only, is going to become necessary, and OI is different from osteoporosis. And the other thing is cardiovascular risk, which was demonstrated in EVENITY, won't be observable in our program because we won't be treating thousands of people.

Right.

So we think, overall, we can hone the program to be more OI specific, but be commercially sensitive that even if there are some price impact, what I'd say to you is the population is so large for OI that it's a very substantial opportunity for us regardless.

Okay. Last question on OI on the time line. When will the Phase III initiate? Likely in early next year, 2023?

No, I think we should be able to get to the Phase III this year.

Okay. Let's move on GTX-102 and Angelman syndrome. Now that's a good topic for now. You just provided some updates on Cohort 4 and 5. In the press release you said there are, I believe, early signs of clinical activity. So what are these activities?

Well, we haven't specified, but what I will say to you is that we're using the Global Impression Scale scoring, right? And so the investigators are scoring positive changes in those -- in the Global Impression Scale. At day 58 and that is the formal test that's after 2 doses. So I think the fact that we're seeing scores that are improving after 2 doses is encouraging. However, we escalated -- we also noted in the release that we escalated -- the dose is escalated in Cohort 4, which tells you that we didn't have 2 -- the patients didn't have 2 domains of 2-plus or better, right? Is that right?

Yes.

So it gives you kind of a range of what you think what we're seeing. We see in multiple domains. So -- and each patient is a little bit different. But we're encouraged that we're seeing some of the activity. And I think that we haven't accumulated enough drug yet. We're going to be -- as we add and get to 4 doses, I think -- and let that drug work, I think we'll see better outcomes as we go. So we're happy with the direction, Edwin, just giving the drug doesn't cause this problem, right, and giving it 4x doesn't cause the problem. And therefore, our thesis that this is mostly [ c-mag ] space that's still intact. And the fact we do it safely, I think, is encouraging. So...

Okay. So U.K. and Canada, I believe, we have a higher starting dose than the U.S. And you don't have any problem there. I guess, the U.S. cohort should be easy. Is that a good thinking?

Yes. It should be easy. We're still going to do the 2-milligram dose we agreed to with FDA.

Yes.

But our hope would be by midyear, if we collect enough data on the dosing regimen ex U.S. plus some additional work on the original patients, which we are doing to help manage FDA's questions, we think that combination data could help us come back to the U.S. and do -- and get those patients to increase their dose, right? And particularly also get the original 5 patients back on being treated, which are now not being treated. So that's something we should be able to accomplish midyear, we think, with the information we get.

So you mentioned that first 5 patients. Do you continue following these patients? I think it should still provide valuable information for you, right?

Yes, we have continued to follow them, and we know that -- and this was expressed by the investigator that some of the improvements haven't gone away, that seem to be sustained, some improvements. So it's very possible that once the neurons get long-term potentiated like trained and learn that they can kind of hold on to it. So while we lost some of the effectors, some things have seemed better -- still seem better. So we're encouraged by that, but it's just sad to have people to put themselves at risk who want to get treated and can't get treated. But we're working in the process and we'll -- my goal is to get them treated this year.

Okay. For Angelman patients, we know there are multiple domains to assess, right? Obviously, communication is one of the key endpoints for AS patients. Just out of my curiosity, how are the expressive communication measured? Are these subjective or objective? Or what do these tests look like?

Well, expressive communication is being assessed in actually different -- there's different endpoints looking at different ways by different observers. So the Bayley's has both expressive and receptive communication scores, which we did put out for on individuals. By the way, I've never seen the Bayley's change for any disease they've ever studied. So this is rather surprising to see changes in the Bayley in such a short time. So the Bayley's is one objective. That's psychologists' administered test of patients' expressive communication. The second is the CGI score that the investigator does and that has a series of things they look at in making a decision on how to score them. So that's taking CGI score for communication. And the third thing is the caregiver score, which is the ORCA, which is a special instrument developed for Angelman by FAST. And the ORCA is validated for Angelman that is an observer-based scoring system, how to pick what are they saying, what are they doing, and so there is criteria for each score numbers. So it's not like, yes, they're doing better or not. There is some basis for the choices. And what we said in the other data is we had evidence of benefit in all 3 systems by different observers, psychologists, PI or parent. So we feel like there was a consistent pattern of improvement that wasn't dependent on the observer and using 3 different instruments.

Okay. Is GTX-102 designed to be a chronic therapy? I know you are giving patients a 4 monthly dose. And then for maintenance every 3 months. So in general, do ASO stay in the cells and are these functional for a long time?

They are in fact functional for a long time in the half-life, I think, in monkeys is weeks to month or more. And they have these locked nucleic acids on the end that are not very well digested, so they hang out for a very long time. So they are weeks to month in the monkeys. So our expectation is that you probably can go even less than every 3 months. Every 3 months is probably on the low end of the time. But we're staying with that until we get efficacy optimized. But it could be every 4 to 5 months might be the time frame where you would -- the long-term outcome for dosing. We say that also because when you looked at loaded patients and their treatment effect, it took 4 months, 5 months before they lost the effects that they had gained, right? So you can use that withdrawal effect on the 5 patients to kind of gauge when they need to get dosed again. And because of the mechanism, we're knocking down this antisense or turning on expression, the reimplementation of imprinting and suppression takes time, too, right? So when you talk about the biological response of losing effect, it's both the loss of the oligo, it's also the time to reestablish imprinting and then also they have a neurological effect of that imprinting, right? So we want to dose based on the pharmacologic time course, right, of the impact. So I think 3 months is probably at the low end. It's probably more like every 4 to 5 will be long-term maintenance when we finally get there.

Okay. Let's switch to gene therapy. First, DTX401 and GSDIa. I know for the Phase III design, you have a co-primary endpoint, right, glucose control and cornstarch reduction. Talk about this co-primary endpoint? And what are the data so far? Yes.

Yes. What I would say to the group is I would look at this as mainly as cornstarch reduction. That's the big factor. But we want a cornstarch reduction that's done without harming glucose control, right? You can't reduce cornstarch and [ have them hypoglycemic ] all the time. That -- so the point of the other -- or the monitoring has to do with we can't lower starch and have adverse impact in it, right? So it's -- whether it's a co-primary or just implicit in the primary, the point is safe cornstarch reduction without causing hypoglycemia. Does that make sense? So I would look at it that way. The CGM part or whether we use glucose -- other types of glucose monitoring is basically about verifying that we're not harming the patient in the process of lowering their starch.

Got it. Got it. So...

Cornstarch reduction the FDA has brought into, they conducted their own patient listening session. Just like the EMA brought a patient to our meeting with them and the patients are telling them what -- they told us, which is the starch is the biggest pain in their life. It's the gun in their head that they carry around with them all the time because they have to avoid being shot. So basically, it's the thing that is a tremendous burden on them, but it's more than just eating starch. It has to do with the fear about not eating starch because something is going to go wrong. Does that make sense? It's more than just the active eating starch. It has to do with the fear coming from if I don't get my starch or if I do or if I'm in the wrong place or I forget it, the idea that I am at risk all the time. So I think the FDA talked to enough people and got comfortable with that, which was our finding. I mean we talked to patients to come up with our plan, and I think that's what made the most sense.

So for a successful trial, what level of cornstarch reduction is considered positive for the Phase III?

Well, we are using a continuous variable analysis, which means we're not setting a threshold, but we may certainly propose a definition for what's clinically meaningful. Based on data we have, I'm certain that 50% or more is meaningful, but the people that were in 30%, 40% range still felt it was helpful to them, important. The average we are seeing is more like 60%, 70% in the short period. But, Edwin, if you look at patients over time, they continue to go down the longer you go. So it takes a little time for their metabolism to adapt to a low starch environment and to reduce the amount of insulin they produce. But I certainly would think of greater than 50% as being meaningful. And the 60%, 70% that we saw in the other studies so far at 6 months or so, I think, is pretty good. At 1 year, we were many patients. We're at the 80%, 90% range, right?

Okay.

So it's somewhere between there, but I believe 50% or more is certainly meaningful, but we haven't set and agreed upon a precise threshold, but the endpoint will be analyzed as a continuous variable.

Okay. Let's turn to GTX-301 and OTC deficiency. I know the FDA had some questions regarding the ureagenesis assay. What's the questions? And how are you going to address that?

Well, they look at that test as being like a biomarker and they don't feel that it's been validated as a biomarker. The FDA doesn't think that any biomarker has ever been validated for anything. So that's kind of what I would call standard operating procedure for rare diseases. Of course, it has been validated, Edwin. No one's ever done that or had a just treatment that could fix the ureagenesis, right? All the other drugs are bypass agents that measure ammonia. So of course, there's no effect on ureagenesis of those drugs. So we're blazing the trail. That means making FDA learn things. In this regard, they feel like it's not clinical as a benefit, and therefore, are not averse to us studying it. They just don't want us making decisions or they don't want it as a primary. And it doesn't matter. We'll put it somewhere in the program. We'll have it as an endpoint and evaluate it because we know scientifically it means something. It's telling us about the gene therapy's biological action in the patient, which to me is important.

Can you just check ammonia at the direct environment [indiscernible]

And we are, that's the primary end point now. But the thing you have to understand about ammonia is that the patients that have OTC are being treated. They're on bypass agents, on severe protein restriction. So they do that to get their ammonia down. Now if their ammonia were rising, they would be getting into trouble and end up in the ER. So everyone's on treatment. And so the amount of ammonia they have is already being reduced by ongoing treatment. So if you look at our trial, we required their ammonia to be less than 100 to be in the first trial. Even so, we had 3 patients out of the 9 during the 24-hour monitoring that exceeded the 100 micromolar threshold. They had 100 to 200, right? And for the next trial, we're allowing patients up to 200 micromolar in their baseline. So we're going to have more high ammonia patients who are more having trouble maintaining control on drug. So that should help our ammonia primary endpoint having more patients who are running high. When you look at those patients, ammonia goes down very quickly at 6 weeks and stays down, right? So the effect on ammonia is very profound. So -- but it's going to be variable because we are highly dependent on their other treatment and how compliant are they, right? Does that make sense? If we didn't have other treatment ongoing, it would be easy. But because you have to deal with ongoing treatment and because high ammonia is dangerous, we can't take them off their ammonia just to see how it works, right? So we have to do the gene therapy and then withdraw the drugs and then the diet, right? So the other endpoint is how many patients can we withdraw their drugs and diet on safely, right, without increasing their ammonia. And that will be another co-primary. So while some patients have ammonia reduction and the hope is that, that would be associated in those particularly that are, let's say, more normal ammonia in the beginning because of good treatment that they can get off their drugs and diet and in significant fraction get off their drugs and diet and give us the outcome we're looking for, which is basically a treatment that eliminates the need for protein restriction and dietary -- and drug usage.

Okay. Let's touch upon UX701 and Wilson disease. First question is, you used a modified truncated version of ATP7B. So tell us it's as good or as functional as the full version? And also, I think this is the AAV9 vector compared to AAV8. Well, what's the difference? What's the advantage?

Yes. So we used -- we studied several different truncated versions by the way of it. And there are several of them that work, by the way, Edwin, and they all can work. The one we picked, we think, would work better and would have better regulation ultimately. And in AAV, it worked better than full length. And part of this is because it's packaged better, we think, but it didn't look like a compromise from full length in terms of activity, the one we used. What we're doing is not the same as the Pfizer version, right? So we have made the one that we are making and that works, but we are obviously different. But I do think both can work and we had results from both. We -- in choosing AAV8, AAV9, we're working with AAV9 in this case because we were trying to optimize distribution across the liver for detoxification of the copper. 8 is a very good vector. We have it for 2 of our programs. We've been very successful with it. 9, if you look at the comparisons, could get more even distribution potentially. And in our hands, gave us a little -- a significant improvement in the monkey compared to 8, a little bit more improved. We're at doses, though, that are hepatic doses, right, not muscle doses. So the safety issues you see with very high dose AAV9 we don't think will be an issue. We're well below the doses that you see that problem. So with a calculated improvement on the degree of delivery of this particular vector across the liver and that -- in packaging this vector. So we are using the HeLa producer cell line system for it. It produced very well. We made 2000-liter run. And with that run, we could treat essentially all the patients in the Phase II portion of the trial with 1 run, right, which is substantially better than other where we are in the triple transfection system. The AAV9 package well and also produces well. So it also has a little plus there too.

All that makes sense. I might skip the questions on commercial product, as we don't have much time left, but I assume you will give us Crysvita guidance in the upcoming conference call. Am I right?

Yes, we'll provide our usual what we did last year, which is the flash sales and guidance for both Crysvita and Dojolvi because Dojolvi has now been 6 quarters out, so we'll give you guidance for both.

Okay. I look forward to that. A few quick questions on business development. We just learned that commercial deal with Regeneron. Talk about the opportunity of Evkeeza for the company and which territory are you going to focus on first.

Yes. Well, first of all, Regeneron is a top-tier player in the making of powerful monoclonal antibodies, right? There's no question about that. And when so we always want to work on products we're going to be proud of. And I think Evkeeza, as a new mechanism of action in ANGPTL3 target first had potent effect in HoFH and a mechanism that's really, I think, a superior mechanism in terms of directing the LDL remnants and part of the pathway to the liver by a different path receptor because they're missing LDLR. So the fact that does that allows you to get the same effect of LDL receptor-based uptake, but through a different receptor. And so it's a very clever reengineering of the bypass of the way lipid normally flows, but it does it in the right way. And then the mouse model dramatically improves atherosclerosis. And in humans, in their own genome center has shown that patients mutations in ANGPTL3 have substantial improvement in cardiac outcomes. So we feel like this is a very powerful biology behind this. In HoFH, while it's been studied many times and very commonly, and I'm not usually wanting to chase these kind of things, in this case, this looks like the best class of drugs to treat that patient because of its mechanism. They already did all the heavy lifting, Edwin. It's already approved in Europe. We're taking the ex U.S. territory. It's approved in Europe. So our focus is Europe right off the gate that is getting reimbursement going and getting launch going in Europe. That's number one. We'll do the filings in Canada, South America and also Japan and elsewhere. We have a very good regulatory group -- international regulatory group. They've done a lot of international filings for multiple products already. So -- and they finished a lot of the Crysvita and Dojolvi stuff pretty far down the road now. So there's capacity for us to take this on, which is why we did the deal in a late-stage program because our next approvals of our internal pipeline will be a couple of years out, 3 years out. So we have time to manage and launch this product in the intervening period. So it strengthens our commercial franchise. It utilizes and leverages our global commercial regulatory skills. And we are beginning the process of developing a Japanese entity. So Evkeeza then will be and Dojolvi both can go into a Japanese group. So those are -- that's what we're doing with it. We're really pleased to have a partnership with them. I think the drug is a powerful drug. It also includes an option to execute on the FOP monoclonal antibody.

Yes.

So I think getting 2 powerful monoclonal antibodies that treat genetic diseases and to get the ex U.S. environment and Regeneron as a strategic partner is a -- it's big plus. It's a good deal, and it's not extremely expensive for us as a deal, right? It's a way to step into this, build out our pipeline of traditional biologics with low risk and high potency. And so it's a good deal. And I'm looking forward to working with Regeneron.

Yes. We are not going into details on FOP. I believe it's an ultra-rare indication. But rather, I'd like to ask you a more general question, what are your primary focus and considerations or drivers when it comes to BD?

Well, from a major pipeline standpoint, we're pretty full, Edwin. We have 6 programs plus Angelman make 7 programs in the clinic right now. I asked you how many big companies have 7 programs for them in Phase III right now? We're bitten off a lot. We need to manage it. So our BD pipeline work is not so much of a focus on clinical stage. We will look at commercial opportunities, although this deal with 2 opportunities kind of does fill our needs at this point. When we look at early-stage, we are certainly looking at things in next generation of pipeline. But if you know us from the past that we are an opportunistic company, and I strongly believe in opportunism over strategy in our business that sometimes people use strategy and it actually causes them to walk past an opportunity that they should be picking up. Example would be the Angelman program itself. And when we were not in the ASOs, we were not in Angelman, but an opportunity came across our desk that looked valuable and potent and had a scientific sound basis to it, and we decided to take a leap, right? And I think that will prove to be a valuable step. That's just characterized what we are about. We're about being smart and making good choices. But right now, I'd say we have a pretty full pipeline and a lot on our plate. And so we're going to be pretty selective if we were to do anything further. If anything, it's less likely to be clinical, it would be more likely late-stage, early-stage.

Got it. Terrific. And last, maybe you could remind the investors what we should look to in 2022 and beyond?

Well, as a company, we've now -- we've transitioned the commercial threshold globally and shown that we can do that. And our growing revenue base gives us a solid future. The adding of Evkeeza to that just adds another piece, another stream of revenue for us globally, which I think will give us a foundational basis for growth in the future. With 4 programs in Phase III, we have as many catalysts and high-value catalysts, including OI, which is a huge, big indication. Wilson disease, also a big indication in that pool. And if you look at the other pipeline like Duchenne or other gene therapy, we're certainly deep in gene therapy, one of the biggest players in the space. With regard to our ability to develop platforms, the mRNA work has now finally entered the clinic. And I think that's another area where we can become probably one of the most productive, innovative companies out there because of our ability to find assets to put them into development. So when you look going forward, I would say we're going to be one of the top-tier rare disease companies in the next few years, that we're going to have a diversified portfolio that will be balanced across modes. It will be global and it will have a steadily and rapidly growing revenue base based on the increasing size and some of the opportunities in front of us. But I think that, that strong diversified basis will be appreciated because years are good years and there's down years. But by having solid revenue growth and some lower risk opportunities in play gives us a strength as a company that I think you won't see in a lot of more volatile companies with more limited opportunities that are going after big but high-risk programs only.

Wonderful. All right. Thank you, again, Emil, for joining us today. Really nice talking to you. Look forward to your clinic update later this year. Good luck, and have a wonderful year of 2022.

Thank you, Edwin. Good talking with you.

Thank you.