ProQR Therapeutics N.V. (PRQR) Earnings Call Transcript & Summary

Hi. Welcome, everyone, to the session, Finding a Needle in a Haystack, Drug Development Strategies for Rare Disease. I'm Yigal Nochomovitz one of the biotech analysts here at Citi. And it's my pleasure to have with me this afternoon 4 distinguished panelists from Dicerna Pharmaceuticals, Douglas Fambrough, the CEO; from Eiger BioPharmaceuticals, David Cory, President and CEO; from ProQR Therapeutics, Smital Shah, who is the CFO and CBO; and from Ultragenyx Pharmaceutical, Emil Kakkis, President and CEO. So welcome all of you. Thank you very, very much for participating in the panel. And maybe just to start things off, if each of you could provide a very brief 2 to 3-minute introduction to the company, what does your pipeline look like, what are the key clinical and commercial catalysts that are coming up for each of you. Maybe we could start with Emil.

Sure. Thanks for having us, Yigal.

Sure.

Ultragenyx is a company now founded 11 years ago, developing treatments for rare and ultra-rare diseases. We work on a number of different modes, traditional biologics, small molecules, gene therapy and mRNA, and have 3 approved products in 4 indications in the U.S., [ EMC ] and ex U.S. And in addition, have a set of 6 programs that are in clinical development. We've worked on a variety of different diseases, including bone diseases, neuro diseases, as well as in-born errors, metabolism. I would say one of the common features of these diseases is that they have relatively small amounts of enzyme requirements or protein requirements in order to achieve efficacy. And that's part of one of the key ways we go about deciding what we work on. With the commercial programs. We have been ramping and launching 3 different products for 3 different indications. And I think have done a great job in managing a new way of approaching patient diagnosis, combined with patient selling to allow us to achieve ramping of rare disease therapeutics in a more rapid way. And by using moderated pricing strategy, we've been able to get better policies and actually better access to patients. With regard to our clinical programs, our big drivers these days are 3 gene therapy programs for OTC, GSD1 and Wilson disease. And we also have a major important program for Angelman syndrome and ASO, which has had some exciting data, but also a safety event and it's getting started. The second half, we'll have a lot of study, starting 4 programs in total studies, including an osteogenesis imperfecta antibody setrusumab, which we have high hopes for as being a follow-on product for our bone franchise. In general, we look forward then to continue growing revenue, but also putting play a number of new product opportunities and launching them globally. That's Ultragenyx in a nutshell.

Perfect. Thank you very much. Doug, tell us about Dicerna.

Sure. Thanks for having us on the panel. Dicerna is an RNA interference platform technology company. We have developed the ability to deliver RNAi not just to the liver but to many tissues in the body with our GalXC and GalXC-Plus technologies, embodied those in a series of programs. And out of 15 molecules in development, 6 have entered the clinic. By the end of next year 6 more will enter the clinic between ourselves and our partners. Those include partnerships with Roche in HPV; and Novo in cardio-metabolic disease; Lilly in similar, more cardiovascular as well as neuro; as well as collaborations with Alexion and Boehringer Ingelheim firm for a proprietary portfolio. We launched our portfolio with rare disease, targeted by the ultra-orphaned disorder, primary hyperoxaluria by our GalXC liver technology. We recently had positive pivotal data in our clients to pivotal trial in primary hyperoxaluria type 1. We anticipate filing an NDA for that product later this year. And I'm excited that, that will be the first approved product to come out of our RNA interference platform. Next up is another orphan disorder, alpha-1 antitrypsin associated liver disease, for which we're developing Belcesiran. And that's in a Phase II ESTRELLA trial. And that is something where we control big U.S. rights for. And then, beyond that, we are expanding into a broader set of disorders that includes both orphan and nonorphan disorders. And so we're trying to take advantage of the sort of broad swath of RNAi to attract -- to treat diseases of variety of scales across many different tissues in the body. We're very well-funded at this point in time, we've functionally been cash flow breakeven or sort of functionally profitable company for a few years now, and that looks like it's going to continue. So we're at a really tremendous point for validated technology, broad pipeline, proprietary and partner and the resources to drive that forward.

Thanks, Doug. And Smital Shah.

Yes. Thank you, again, Yigal, for having us here. Very much appreciate you and citi. So I'm at ProQR Therapeutics. We are an inherited retinal diseases company. We're not modality agnostic either. We focus on using our toolbox of RNA-based approaches really to target the disease. It's really centered around sort of what we call 5 pillars. And in rare diseases this is very important. It starts with the patient. So what the patient is, what is the unmet need, what we're trying to solve for. Which takes us into our second pillar, which is that of innovation where we use this RNA toolbox, whether it's splice correction, whether it's exon skipping, whether it's -- if it's a G2A mutation, our RNA editing technology, Axiomer, for which we announced a partnership with Lilly as well yesterday. So we use all of these different modalities to really target the disease. It then takes us sort of into the translation piece where our objective and goal is through in vitro work our organoid models that we use for the eye, that allow us to effectively predict potentially doses that could be effective in the clinic, particularly important when you don't have animal models. So we've used that for both of our lead programs right now as well. And then that takes us to sort of the development piece where some of it, you make that [indiscernible] in rare diseases, having the relationships across the board with KOLs, and that's a big part of what we focus on. And hopefully, that would take us to that fifth part, which is commercial, which kind of brings us to the lead programs that we have. The first disease we target is Leber congenital amaurosis 10. It's a rare genetic disorder, very aggressive form of childhood blindness, for which we are now in a pivotal trial that is slated to read out first half of next year. Our second program is also a debilitating eye disease called Usher syndrome, but more slower progressing. So here we hope to arrest the disease progression of these patients. And that advanced this year, we were very happy, into a pivotal trial as well. Beyond that, we have 2 other clinical stage programs in ophthalmology and a number of more in discovery. And simultaneously, we work also on our RNA editing technologies, Axiomer and Trident. So that's us.

Okay. Thank you, Smital. And David, Eiger.

Thanks very much, Yigal. We very much appreciate being involved in the conference this year. And like many of the other speakers, at Eiger we are developing targeted therapies for serious rare and ultra-rare diseases. We have a very diverse late-stage pipeline with 6 programs. And in fact we have 5 ultra-rare disease programs. Each and every one of the 5 have now been granted FDA breakthrough therapy designation. And for us, as a company, a small biotech company, that's one breakthrough therapy designation for every 7 employees. So we we're proud of the accomplishments that we've had thus far. And again, it is a very diverse pipeline. We actually received our first NDA approval in November of last year, and that was for what we believe is maybe the most ultra-rare disease known to man. And that was with our drug Lonafarnib, a small molecule oral drug under the brand name Zokinvy for the treatment of Hutchinson-Gilford Progeria Syndrome, a point-specific mutation, a genetic disorder that leads to rapid aging and usually death by stroke or other forms of cardiovascular disease by the time these kids are 14. Zokinvy was approved in November by the FDA as the first and only therapy to actually improve survival in these kids. And we've now, since beginning in clinical trials, many years ago, we now have young adults and people in their mid-20s who've been on Zokinvy for over 10 years. And so we're very proud of that accomplishment. Importantly, our largest and our lead clinical program and commercial opportunity we believe lies in hepatitis delta virus infection, and that's with 2 distinct molecules: first, a small molecule, Lonafarnib, boosted with Ritonavir, for the treatment of hepatitis delta virus infection, and that's actually the subject of the posters behind me. We're very proud. We will complete enrollment of 400 patients by the end of the year in the first ever global study of hepatitis delta virus infection, which is a devastating infection. It is an orphan disease. We've involved over 22 countries in this trial. And again, we'll look forward to announcing completion of enrollment later this year. And then right behind it, pegylated interferon lambda will begin registration. We plan to enroll our first patient in a single pivotal trial before the end of the year. And then right behind that, Avexitide, in a very different targeted program for metabolic disease. Avexitide is a peptide targeting now 2 high unmet medical needs, first in post-bariatric hypoglycemia and second in congenital hyperinsulinism, 2 high unmet medical needs with currently no approved therapies. And importantly, while it's not an orphan disease, we discovered proof-of-concept late last year with Lambda in COVID-19. And COVID-19, as everyone knows, continues to ravage much of the world. Pegylated interferon lambda is currently in a Phase III, we believe what could be a registration-enabling study in Brazil, and we plan to have interim futility analysis to read out by end of year. So a lot of activity, and importantly, driving, we believe, towards multiple approvals in the future.

Okay. Thank you very much, David.

So my first more specific question, hopefully, it'll spur some debate amongst the panelists is your strategy for selecting rare disease indications. How do you select which rare diseases you're going to pursue and which ones look interesting, but you are not going to pursue. There's got to be some algorithm there that each of you have in terms of the thought process of where you select and where you don't select. So I'd love to hear your thought process on that. Emil, maybe you could give us -- give it a start.

Sure. Well, we highly focus on genetic disease where we know exactly what mutation is. And our general focus on solid protein deficiencies for which a relatively small amount of normal would give you a normal effect. So a few percent. So that is generally what we focus on. So if you look at our Mepsevii only a few percent of normal that actually was placed at enzyme efficiency state. For GSDIa 3% of normal of that enzyme, a small soluble enzyme. OTC, maybe it's 5% to 10%. Wilson is probably in that same range. We have a low threshold success on the [ soluble ] protein, that's a lot easier to achieve, and you don't have to have a very large expression. So genetic disease, soluble enzyme, low threshold for success. And of course, a bad disease, a disease where there is a significant problem, one that's reversible. And so if you look at our portfolio, you will see, in general, you'll find deficiency states. The only different one is Crysvita. In Crysvita situation, there's a hormone that's extremely high FGF23. In this case a monoclonal is blocking it. But FGF23 is present in small concentrations. And so blocking is actually very efficient and can result in a very big effect. So in that case, it's knocking something down that's high, but that's what we basically look for genetic low threshold for success bad disease.

Very interesting. Doug?

So I think we have a very different lens that we look through because we are fundamentally a technology-based company. So we are, if you will, the hammer looking for a nail. Of course, the old proverb is terribly unfair in people with hammers, right? We're looking for absolute ideal [ dales ] to go with our technology. Now RNA interference, I mean, the first we'd point out, in contrast to what Emil was talking about where you're restoring function, most genetic diseases are a loss of function. RNA interference is an inhibitor technology. And so it's not a match for restoring function. We're really interested in rare diseases where you could stop a biological process and thus have a benefit on the patient. Now that falls into a couple of categories, none of which is, I think, as common as you're sort of straightforward, hey, something is missing, you got to put it back, you're going to add benefit. One would be where you can make a compensatory mutation. So it's that sort of 2 negative, 2 wrongs makes it right, if you will. And that characterizes our RD program, primary hyperoxaluria, where the absence of an enzyme causes the over-production of a metabolite called oxalate, but we can block the oxalate production. There really isn't any negative symptoms associated with not having a functioning metabolic pathway to break down pathway, lengthy stuff anyway. But you just need to get rid of that toxic metabolite which accumulates. And you can use this compensatory mutation there to do that. The other case where you see this is where the mutations cause a dominant negative type phenomenon. And so our second most advanced program, belcesiran for alpha-1 antitrypsin liver disease falls into this category where you have a mutation in a protein that causes misfolding and it causes an accumulation of globules. And the liver disease is a consequence of the accumulation of the misfolded protein. So we can -- by turning off expression of the protein address that issue. So really, we have taken a very targeted approach to look for rare diseases where an inhibition of something can sort of provide benefit. Now rare diseases in general are an attractive area for us because of genetic disease, they are monocausal, right? And you know what the cause is and you know everyone who's guided or guided, you have a definitive diagnostic. That doesn't mean you fully understand the disease. I think that's an important thing to say. Even genetic diseases that look simple, hey, you're missing this, can have a lot of complexity embedded in how the body responds to them, what's going on in the biochemistry of the pathway. But in general, I think those sorts of disorders are going to get a higher probability of clinical success. And so that makes it very attractive to go after. The other element of rare disease is that you can operate at a speed and scale that is very friendly to value creation for a smaller biotech company as opposed to very broad disorders. Now RNAi as an inhibitor technology does give you an entree into the very large disease indications as well. So we've got cardiovascular programs with Lilly and NASH programs with Novo. And I think you'll see Hepatitis B Virus with Roche, for example. But for our own purposes, really choosing those perfect diseases where we know what we need to knock down, where there is a genetically defined population where we can move quickly. That's been our selection ciretria.

Thank you very much. Smital, what are your thoughts?

Yes, we've narrowed it down for ourselves already. We focus on inherited retinal diseases. I mean, but there are still 300 disease-causing genes and multiple pathogenic mutations. So there is quite a selection process that still has to occur. So indeed, we first start with sort of what is it that we're trying to solve for, do we understand that, is it knockdown that we need, inhibition that we need, is it restoration that we need. So we do look at the entire landscape of RNA and then use the -- first of all, is RNA the best technology to use for that, right? Are there advantages that you would have because you don't over-express or under-express, you don't express it in cells that you don't need to. So I think there are significant advantages that RNA can have, and that's really what we try to find. I think important in rare disease is also -- once you kind of find that, and you know that that's the biology that works, is this something that you can develop, what does that development landscape look like. Because in many of these diseases, we are the first ones there. So there is not an actual history established yet. There are not validated endpoints. So there is a lot of work that needs to occur on that. And here's where the platform piece across IRDs helps us because we can take a platform approach to developing endpoints over a whole portfolio as opposed to just one disease. Importantly, will these end points then allow us to look at access once it's available, even if they may not be validated? So we look at that whole landscape of what can we use early in proof-of-concept and then late-stage development. And then the commercial potential of it, although we don't focus too much on it because again if you can develop these, if there is an unmet need, there is speed and efficiency to doing it in these indications, then we use all of those to really come up with what we call our prioritization list among all these diseases that we can go after.

Okay. Thank you. And David.

It's very interesting to hear the different approaches for each company. For Eiger, I think we're a different approach. And in Eiger's case, our first goal really was to begin identifying rare diseases with high unmet medical needs, as you've heard previously by other speakers. In addition, those unmet needs in our case have each had no approved therapy. And in many cases, these are life-threatening disorders and the high unmet medical need is clear. Second, we began to look for druggable targets that from a biology or a pharmacologic point of view made sense and was defensible. And then third, we went out and sought to find well-characterized assets are well-characterized drug candidates that we could quickly repurpose and move into the clinic to, as Doug mentioned earlier, one of the things that you hope to benefit from in orphan diseases is potentially a faster pathway in the clinical development and regulatory realms. But our goal, has always a fast pathway towards Phase II proof of concept. And then registration. And I think our lead program exemplifies that quite well. Lonafarnib is an oral prenylation inhibitor. It blocks the attachment of prenyl lipid to proteins, which is necessary for normal cellular activity. In the case of HDV, the delta virus uses that, hijacks that pathway that is in our host systems to complete its replication. And ultimately, that's what led us to Lonafarnib, which was being explored initially as an anticancer agent to block Ras farnesylation. So we were able to take a very well-characterized compound that had been in over 2,000 patients immediately into Phase II to begin proving concept in a high unmet medical need disease area in hepatitis delta virus infection. And I'll just add one other point, somewhat serendipity. But along that pathway we discovered that there was another disease population in progeria that is the result of a prenylated proteins, progerin, which is an aberrant protein that ultimately accumulates and leads to this rapid aging disease known as progeria. And so along the pathway of developing Lonafarnib for HCV, we were able to prove a survival benefit with Lonafarnib in the treatment of Hutchinson-Gilford progeria syndrome and actually win our first approval in that indication, as I mentioned earlier, just late last year.

Very interesting. Thank you, David. So my next question hopefully will also spur some good debate. Curious, what are the key trial design considerations for rare disease trials? What is the strategy for selecting the right endpoints, especially for diseases where there is no established regulatory precedent? And what are the key pitfalls to avoid when designing trials for rare diseases? Emil, I'm sure you'll have plenty of say there.

Sure. I think one of the key things that's challenging rare disease is the fact that there's tremendous heterogeneity. And the rarity leads to the inclusion of a wider variety of types of patients. And therefore, picking a clinical endpoint becomes difficult without high selection of the population you study. And the tendency for the agency is to focus on clinical endpoints that they have experience with, and therefore you have the problems of actually designing study where that can work. For Mepsevii or MPS 7, we had trouble defining a single endpoint in fact, and used a multi-domain responder index. Now the FDA is not particularly happy or agreeable with that approach, but the truth is, it's a powerful approach for dealing with heterogeneous diseases. And I think it's an approach we've been promoting and published on and I think will come forward as a much better way of capturing total clinical benefit. In general, biomarkers should be the way we're doing this. I think there's a lot of situation with biomarkers, particularly biomarkers that are primary disease activity biomarkers, right, not downstream paths of physiology but upstream disease activity biomarkers are more reliable and should be more easily qualified for metabolic rare diseases. And they would actually lead us to a much more rapid development strategy and a much easier path in dealing with patient heterogeneity. So the number of things we watch out for is how heterogeneity can really destroy power and power assumptions. And therefore you need to properly manage the patient population you're bringing in, the endpoint you choose and statistics. And in all of our statistics, specifically with -- we try to focus on continuous variable, always killing all the power, multiple assessments over time to increase the power and an approach that we can essentially double the power and reduce the variation, and this will help give you a greater shot of success in these types of programs. So if I had to pick one thing, heterogeneity is the thing that really kills people, and it's one of the hardest things to manage.

And if I could just follow-up quickly, Emil, you mentioned biomarkers. How do you build out picking the right biomarker and having confidence that it's reasonably likely to predict clinical outcomes?

Well, it's whether you have confidence or FDA has confidence. The challenge is with FDA it's been very hard to get them confident. I was successful with PKU in the original Kuvan program getting them to accept phenylalanine, but we did a huge meta-analysis of the literature on diet control and fee outcomes, which was able to give them the kind of data they like, that kind of data doesn't really exist usually. For Crysvita, we were able to get acceptance of our radiographic X-ray marker blinded reading scoring system. And in that situation, the biomarker in their mind was more directly related to the disease, the rickets and the bone effects rickets. And they had some acceptance that rickets itself was bad because of vitamin rickets and the treatment of it. And so we just need to prove that we can measure rickets, but not that rickets was bad for you clinically. Does that make sense? So that helped Crysvita. But MPS 7, we couldn't get urine GAG, a biometabolic marker which is highly predictive, we believe, of a clinical outcome. And including multiple rounds of data on why that was. And the EMA did accept it. FDA did not. But we designed our program based on the EMA's acceptance. Truth is, qualifying the biomarkers usually requires some relationship with clinical outcome data, which is almost never possible to have in a rare disease. Therefore, my foundation, EveryLife Foundation, few years ago supported a bill called the ULTRA Bill, which was passed beside, I think, the PDUFA at that time which said that the FDA should divide a guidance on how to qualify biomarker for rare and ultra-rare diseases using only pharmacologic and pathophysiologic criteria when other types of data, in other words, clinical outcome data are impossible or impractical collect. Unfortunately, the FDA has still not complied with that law and provided such guidance. And so I wrote a recent stat, news article talking about the Alzheimer's approval, and saying the FDA needs to start approving other neurodegenerative disorders using biomarkers as well, not just the big one, but what about all the little ones for which you won't get a treatment developed ever because it's so hard to use clinical endpoints. So we think there's a lot of room for improvement. Obviously, it's a hot topic for me. I've been working on for a lot of years. And I probably went long, but that's the story I have.

That's okay. That's okay. That's what this is for. Doug, tell us what you think about clinical trial design for rare diseases?

Well, I think Emil sort of covered a lot of ground there that I would certainly agree with, certainly on biomarkers, that's been a key way that we have thought about our, frankly, indication selection. So maybe I would point out some other elements. One is coordination with the patient advocacy community and designing the trail. So we have found that we've got a lot of insight, particularly the secondary endpoint level about what's important to the patients in the disease and that the FDA needs education on that. These are indications for which generally there is little or no FDA experience, and they don't -- they need a lot of education on what's going on with the disease, and it's the patients that have a very strong voice with respect to that. Also, enrollment is a critical issue. These are orphan, ultra-orphan disorders. They're spread around the globe. You tend to meet a lot of sites. Working with the patient advocacy community can really help with enrollment. And so there's a strategy there. That's not necessarily trial design, but in thinking about doing trials, the appropriate engagement and communication, really, I guess, you'd call it directly with the patients when formally an enrollment process is -- it goes entirely through physicians. There's another channel of communication there through advocacy organizations to get the word out of what's going on that can help drive an enrollment process in the trial. So those are a couple of other things to think about in rare disease that don't come up in the same way and with more common disorders.

Thank you. And Smital for inherited retinal diseases. Are there specific criteria that you need to adhere to in designing trials?

Yes, for sure. And I do -- I agree with Emil on the heterogeneity piece, which is true in all of the IRDs as well as to where the patient baseline is, there is not natural history available. So where do you pick the patients? How fast does their disease decline? Even at the same baseline, they could decline at different rates. So when you're trying to do that, it becomes really, really tough, right? I agree with Doug as well, but then how do you restrict that criteria to make sure that you can get the trial enrolled? And how do you build the patient perspective in? So all of these are challenges. The way we think about it is maybe I would say 3 ways, right? First and foremost, to change the regulatory landscape takes a lot. And if you're trying to get that done. So the lowest-hanging fruit in some ways is can you enrich for the trial such that the key endpoint, which is BCVA, Best Corrected Visual Acuity, or your eye chart. Is that something that you can do? For our first trial, it was great because we did see a strong response in BCVA. So that piece was pretty established. As we think about the Usher trial, this heterogeneity became quite a key. So we had to separate the 2 trials. One, looking at BCVA for advanced patients where you can actually measure. And then you have to look at a second trial, both independent where you're looking at perimetry measures. So people whose disease is not as advanced. So they will not show that in BCVA. So if you combine those 2, you're not going to get to that [ sad ] outcome. So that is also something that we do. Now as we're developing this as a portfolio, what we also try to look at other interesting endpoints that we can study that build one on top of the other, which even not validated right now could be for the third or fourth or fifth program. So I think that's a view we can have given we work in this. I think the toughest part is the quality of life measures, I would say, which are important from an access point of view. And I agree with Doug that involving the patient organizations, just the patient voice, we do that through a patient steering committee early on as soon as we start thinking of our target as to what are we trying to solve for. And that becomes quite interesting. I mean if you think about a PRO for ophthalmology, it asks you to say, do you use your walkman where nobody has heard of a walkman anymore. Can you use your power tools? Tell that to a person who can't tell light from dark. So how would you use such a PRO to actually measure quality of life for patients that cannot see, not even on the eye chart? So how do you morph that? So we try to build in quality-based measurements, which then allow from the access point of view, but may not be as relevant to date from a regulatory point of view, hopefully could be down the road. So that's sort of the approach we take.

So David. David.

Thanks. At Eiger we definitely had our challenges and several I think very good experiences with regulators across a really diverse set of programs, none of which had a clear pathway with regulatory agreement or endpoints. And I'll give an example. The first product our company was able to get approved, Zokinvy, was for the progeria patient population. And that NDA was based on 2 studies which were open-label studies, run at Boston Children's Hospital, basically in an academic fashion. And the primary and secondary endpoints for cardiovascular and ability to thrive Pulse Wave Velocity and weight gain and other things. And when the results of those studies were shared with the agency, they said that's good. But can you keep these kids alive longer. And so based on extensive analysis and I think really good collaboration between Eiger, the Progeria Research Foundation, NIH and the FDA, we ultimately were able to submit a really tight analysis showing a survival benefit, which led to an NDA approval for Lonafarnib or Zokinvy for progeria, a very unique set of circumstances and a pathway that ultimately has what we think could be a life-sustaining therapy for these children. For our other programs, for instance, HDV or hepatitis delta, the surrogate point is an important one. We know if you reduce viral load in most viral diseases, especially hepatitis, you can keep patients alive longer. Their liver enzymes usually normalize. And even if it's not curative, you can keep patients alive longer. And so I'll just end by saying that for our lead clinical program we were able to negotiate with the FDA a pathway that has a primary endpoint, which is a composite, which is a 2 log decline in viral load and ALT normalization. That's not a cure, but it's not necessary. It keeps patients alive with the goal of ultimately getting them to a cure. And so that was a really good collaboration with FDA that we're very proud of and again excited to continue executing to get to ultimately Phase III results.

Well, David, you must have read my mind because that's a great segue into my next question on FDA. As you point out, a good working relationship with the FDA is critical not only for rare disease, but obviously for all diseases. So I'd be curious to know from each of you, how has your team leveraged the FDA interactions to accelerate clinical development for rare diseases specifically? David, do you want to continue that answer? Or we could move to one of the other panelist.

Yes, sure. And I think there have been many war stories about dealing with regulators in all of our past. I can tell you at Eiger, I feel lucky that we've had a really good collaboration with every division at the agency that we've worked with, not to say that it's been easy every step of the way. Somebody mentioned earlier education is required, and there's a lot of negotiation, I think, back and forth, especially for an orphan disease where the patient population is heterogeneous. And you have no pathway because no drug has ever been approved in that specific disease. And I think the approach of being patient and trying to be transparent in everything you do, at least from our perspective, has led to really, really good negotiations with the agency. We don't always get what we want, but we're usually able to negotiate what we think is best and in the best interest of the patient population that leads to, hopefully, an agreement on what is safe and effective. And so our pathway thus far has been, I think, blessed, and we're lucky.

Great. Emil?

I think it's -- one of the key things about understanding the FDA is that it's not one thing, it's not one FDA, it's different review divisions and they all have their own character and type. So with the -- for example, the Bone, Reproductive division, with Crysvita, we were able to leverage our developing work on Crysvita there for XLH. And we were able to leverage that for an approval on TIO using an open label Phase II study, essentially using the XLH information, that information we developed with them where they were, let's say, less comfortable with the phosphate biomarker and the outcomes and used that data to leverage it to getting a TIO approval now with a lower amount of data required, just a Phase II open label study and get that indication added on. So I think that's an example where building good relationship, fulfilling their understanding can lead you to a next step, which is a more irrational and appropriate regulatory answer. In other divisions, there's been a lot of changes and particularly the regulatory structure of the redivision at CDER have changed in the last year or so related to Janet Woodcock's desire to specialize in review divisions. Now in the long run that will be better, but in the short run it also created some uncertainty and some changes, and I think that's impacted some review programs, particularly in the inborn errors area where there was some significant changes in who was there. So we manage different agencies and leverage them differently. And it's definitely a heterogeneous FDA as well as the patients being heterogeneous.

Good point. Smital?

Yes, no, I completely agree with all that. I think for us we obviously deal with one division, given it is ophthalmology. So that makes it marginally easier. I think it is really about data-driven engagement because if you ask a question without data, you know what the answer is going to be. So it really is about bringing them along through that. And I mean, we talk about the FDA, but there are other regulators too. So we develop it for -- globally. And generally, when we want to do the trial, it's a global trial. So reconciling sometimes between the 2 sets of regulators also poses a challenge in and of itself because there have been instances in which one asks for something, and the other one asks for something that's actually in conflict with that. So you kind of have to bring all of them along. So at least our approach has been -- and I speak for our Chief Medical Officer, this is not my area of expertise. He has had 4 or 5 different approvals in ophthalmology under his bed. So he has always sort of kept a very strong dialogue with the regulators from the beginning, both sides of the pond and outside of that as well. And really, even as we have preclinical data, we've engaged them when you take Usher as an example. We were thinking of this, we were thinking of dose escalating here. The great thing about the ophthalmology division and Wiley Chambers in particular has been he's been very accessible. And in fact, he is one who believes that what is the point of a breakthrough designation, you have access to me anyway, just call me or text me, and he's available. So we've been able to engage him very well, thanks to, again, our CMO, who's been able to do that. So I feel like it as a relationship that you -- it's a strong one. You've got to manage it, very key important stakeholder. That said, they are not perfect either, and they need to be brought along. And they're open to that, but you've got to do that with some data and finesse. And I guess I'm thankful I don't have to do that.

Doug, thoughts on the FDA?

I would underscore the value of breakthrough designation. We talked about some of the challenging issues with regulators with respect to endpoints and diseases that haven't been -- haven't had endpoints defined for them. Some challenges, for example, in PH, we needed to figure out how to sort of jointly develop in the same trial for multiple indications. And having the breakthrough designation really facilitated a level of conversation with the FDA to work through those issues in a very successful way where ultimately our biomarker became an endpoint for full approval, not just accelerated approval. And we were able to define how we could manage going after multiple indications at the same time in a single trial. So that level of communication that the pathway has provided, breakthrough designation has provided, has -- was materially valuable to us in defining our strategy in PH.

Understood. Yes, sort of anticipated my next question on breakthrough and other designations. Emil and David, maybe you could chime in. Do you see these designations as valuable to breakthrough the orphan designation, the fast-track designation? How much do they matter for you?

Well, I think orphan designation is a basic -- your base of exclusivity to establish that in the tax credit in the long run assuming you get approval. So it's a solid basis. It's unfortunate tax credit has been reduced to 25%. And I really think that should be brought back to 50% and maybe capped, but it is important as a basic starting place. I agree that breakthrough therapy clearly can change the dynamic. It also is kind of giving you a leg up on their review of your whole program, right? They're making a decision, right, that they think you've got an approval product, and that changes the way they approach you. For Crysvita, we had a lot of debate about needing a Phase III study for peds and adults, for example. We showed that data really of breakthrough therapy designation, they let us file without a Phase III completed for peds just off of Phase II data, and we completed the Phase III later. That wouldn't have happened I think without the breakthrough therapy kind of compelling them to make a decision of an agency and saying this is important now let's do something for these patients. And so we think breakthrough is clearly important. They've gotten a lot more applications. They've gotten a little tougher on accepting them too. So I would also see there are situations where it may not help you. If you're already starting your Phase III and you're there, you have to run the Phase III, then the breakthrough therapy is really a bad [indiscernible] at that point because they're not going to -- you're already doing a Phase III and you're heading there. But I think the really key thing is you can use a breakthrough therapy designation to file off of Phase II or earlier stage. To me that is a huge win, for patients and for the company. And it's the one thing I think breakthrough therapy can do or could do that would change things for rare disease patients, particular types of the ultra-rare, ones that we're working on.

Yes. I would echo what Doug and Emil said, the breakthrough therapy designation for us, for instance, for our first approval definitely gave us, we believe, much more access and dialogue with inborn errors division and also allowed us to file for an accelerated review such that review time was 6 months and that was invaluable. And our other breakthrough therapy designation programs. We've enjoyed a level of dialogue with metabolic division, with Division of Antivirals that I'm not sure we would have had without, and we look forward to taking advantage of it as well, hopefully, in gaining accelerated review for those programs as well.

Got it. Thank you. So just in the remaining moments of the panel, wanted to squeeze in a few more questions on the commercial side. Talk about what you need to get right when launching a drug in the rare diseases -- in a rare disease market. What are the common pitfalls to avoid when launching a drug in a rare disease? Emil, you may...

Well, I've been involved in a lot of launches. And the problem is with rare disease launch they tend to have what's called the slow build. The slow build though is really driven off a fundamental problem, which is the patients don't even know you're approved and the doctors don't even know you're approved because they don't -- it's very hard to get the outreach to get them be ready. And patient groups don't necessarily -- they often have less than 10% of the patients with the disease that are actually in the group. So it's not exactly I go to them and everyone finds out what's going on. The truth is patient find is a really critical thing. And what we've done differently at Ultragenyx finally. And once you're in charge, you get a chance to do it all, right to do what you want to do because we have a team that's on the patient-diagnosed liaison team that's as big as the sales force. And they go out a year before launch with launching the disease, not the drug, the disease. They only talk about disease state in diagnosis. And they go out and identify and create a landscape of all the doctors that have patients and drive their diagnosis, proper genetic diagnosis everywhere you can, build up the funnel and then launch happens. And now you've got this funnel full of patients and doctors found, and your sales team is simply taking patients they know, talking about drug, getting them on drug. And then your patient -- this team is going off to the next patient, fine, and they're filling the funnel, and we've been doing that with great success with Crysvita. We loaded up with a few thousand patients for the team to launch and they continue now doing the outreach for adults and that -- one-two punch is a really powerful way to drive revenue and find. And the key thing that people don't do is invest enough in patient diagnosis. And the thing I will tell you very simply, the calculation we did is it turned out to have a 36-person patient diagnosis field team, costs $9 million a year. That cost was the ROI breakeven was if they found only 50 patients for treatment with Crysvita. Only 50 was breakeven, and they find hundreds. So the value of being able to find more patients and drive that is actually dramatic. And that's why I think Crysvita has done really well and found the patients and kept the growth going. So I would say that's like the #1 insight we've had. We had an opportunity to finally do it differently. And it's going well. And it's always going well too for the same reason.

Very good. Doug, Doug, what are your thoughts? You're close to launching, albeit with a partner, but you are close to launching.

I don't think I have anything to add here. We look forward to having some stories later.

Okay. Fair enough. Fair enough. Anyone else want to chime in on that one?

I'll comment since we're, I think, in the next stage of our U.S. product launch for Zokinvy for progeria. Again, this is probably the most ultra-rare disease known to man. We had identified 20 of these children and young adults in the U.S. And from Eiger's point of view, working closely with Progeria Research Foundation, setting up a managed access program to ensure product to all of these patients, even before approval, allowed us to ensure a much more smooth transition from clinical product into commercial product. And we're planning the same thing in Western Europe as we expect EMA approval as early as later this year. And then for HDV, I think the biggest issue for us is, and this is common in many orphan diseases, it's awareness. And to Emil's comment earlier, having a team out there facilitating and driving awareness and diagnosis. For us, that's our next big hurdle in the hepatitis delta virus segment. And we're somewhat lucky in that hepatitis delta virus while it's the most severe form of viral hepatitis, it's always a coinfection on top of HBV. So we don't find patients de novo. We just need to enact the guidelines and ask physicians to test every HBV patient for delta infection and point in fact, that's what we're doing.

Yigal, I was going to add one other thing.

Sure.

Because I -- mentioning the access program I think is really important. If you're launching in the rare disease space with expensive drugs, you have responsibility to make sure people get access. And so for our programs in the U.S., we guarantee that patients will get access one way or another through insurance or whatever the system is, we make sure that they get covered. And we can't leave anyone not covered, and that's part of how we price and operate. So there's no patients not getting Crysvita due to financial reasons or [indiscernible], right? We guarantee that. That means we use whatever means we can to help support patients to get insurance, get what they need, or, in some cases, provide free drug access. And I think it's a really important part of the responsibility in the rare space if you're commercializing, to take care of everyone, especially when you have drugs that are expensive, right? And you don't want that to become the factor that people go after, that you got to take care of patients. And if you do that, then things will go well.

Well, Emil, you get the last word. Thank you very, very much. And thank you to all the panelists for participating. Very interesting insights and discussion. Best of luck for the rest of 2021. And we look forward to having you here again next year. Hopefully, we'll actually be in person for a change.

Thank you.

Okay...

Thank you.

Thanks for having me.

Bye.