Conference Transcript - RARE 2026-06-09

Operator

All right, welcome back, everyone. Today we have the pleasure of speaking with Emil Kakis, President and CEO of Ultragenix. Emil, maybe to start just to level set, you are sitting in front of key phase three Angelman data in the second half of the year on the potential path to profitability in 2027. So in that context, how is Rare positioned from here in the second half of the year and then over the next few years, and what are the company's key priorities?

Emil Kakkis, CEO

Certainly, we... Certainly happy to be here and be talking with you today. We started the year off with a difficult problem with missing an OI at Phase 3, and that was tough. But we have a lot more than OI in the program, in the company. And so Ainsman is the big driver of what people are most interested in. It's the biggest upside product. We've done a lot of work in preparing for that Phase 3. We put out some data at the last quarterly call, which talked about the long-term Phase 2 data. That phase two data shows that patients continue to gain ground over three to four year periods. They have durable effects and that the safety is excellent and there's no cumulative safety concerns or issues arising. And it also tells you something even more important, which affects us commercially, and that patients and parents are interested in keeping getting intrathecal infusions every three months for years for their kid to see the benefit they're getting. And there's very few parents who keep going for intrathecal injections for a drug for no reason. So it tells you something that people are staying on the treatment. It tells you this is a viable treatment that's really helping their kids and it's worth it. So that's what we got out of that. We did a lot of work on our phase three and operationally, which was bringing forth sites that we had already tested in that phase two study so we knew they could do the test, we knew what the patients were like, and we had ironed out any particular executional issues. We brought in a third-party tester for the Bailey testing score, which is one of the primary endpoints, to make sure that was done to perfection. and we've supported the sites as needed now to be able to handle the workload and workload. And so it's gone well, and we're really excited about being able to enroll in six, seven months and to now be looking at patients finishing the study. We have already had patients finished and cross over, and we continue doing that process. Last patient in was last July. 48 weeks takes to sometime this July, June, July. And then there will be some weeks to months of cleaning, locking, preparing, analyzing data before we release. We haven't put out a specific timeline. But I think we're in a very good position with the phase 2 data showing us long-term durable benefit and long-term gain and a phase 3 study that's been executed well. And finally, we've added the Aurora study, which will look at the older and the younger patients and the other genotypes to fill out the story together, I think putting us in good position. It puts us about a year ahead of everyone else, and I think we're pretty encouraged. So that position is well for big upside, but if you talk about revenue and cash, the two gene therapies probably have a more immediate impact. We've been investing in the launch of both programs, expensing product that we've created and put on the shelf, and some of our burn in the last couple years have been to make products sitting on the shelf, so it's not burn that's gone. It's sitting there as product. When we... Our Purdue dates are in August and September. So far, reviews are going fine. And if we get both approvals, we'll have two PRBs, you'd expect, which have been selling for very significant sums of money, which will add to our cash balance sheet and put us in a good position. But in addition to that, we'll be launching most of those programs And Sanfilippo is an urgent disease, and of course there are many patients interested in getting treated, and so we had a lot of inquiries both in the U.S. plus also ex-U.S. It's a lot more like Zolgensma for SMA, right, in terms of the urgency. And we think that will drive uptake fairly quickly for Sanfilippo syndrome. For GSD1A, it is an urgent disease, maybe not as urgent as Sanfilippo. They're not losing their brain, but the idea of taking starch every few hours forever is tough for patients. They want to get off that treadmill and put away some of the fear they have that every day they could die if they miss a dose of their starch. So both of those, I think, are programs that will do well. And I think our gene therapy franchise is not valued at all, I think, at the current lane. And so if you think about that much cash brought in plus the revenue, the swing between this year and next year will be very substantial and put us in a position to launch Angelman well. But finish 27 with a potentially profitable year with three new products launched and then other products in late-stage development, which I think put us in a really good position for the company going forward. So I look at this year as we get to third, fourth quarter, has been kind of transformative for the future of the company. And I think on top of the base business, which is earning in the mid $700 million range, has been growing by 20% a year the last few years, I think we're real well set up as a global company to take advantage of those three products launching globally, which we own the full rights to. I think that puts us in a position to really transition to profitability but it's sore past it. And so I feel good about where that is. It would have been nicer to start with a positive OI study this year, but we take the challenges that are put before us. It is biotech and it is hard. So I feel good about where we're going, and I feel like I think it should be a good year for us, and I think at our current valuation, I think it should be a clear opportunity for people. Sorry for taking a very long period of time.

Operator

No, no, no, that was helpful. Thank you for laying all that out. I guess maybe just quickly on the path to profitability before we dig into Angelman and some of the other pipeline products. You have two potential PRVs that you mentioned. I guess how do you plan to kind of time the monetization of those to kind of bridge that gap to profitability potentially in 27?

Emil Kakkis, CEO

Well, we certainly plan to sell both of them. And the exact timing, you know, could depend a little bit on what makes sense. You know, certainly we could sell one this year and one next year to manage the burn. But I would, you know, I think Howard and I will have to talk through it, but I don't think we want to overthink it. I think cash and the balance sheet are what we need to do. But you could look at how that affects profitability next year. I'd also point out if Ainserman's positive, that's another potential PRB, which could be in 2027. So that stuff could put us where we want to be. And I would say to you, we could do it this year, next year. But if we are able to achieve $200 million for each of those, which is what people have been getting close to at this point, you know, it's a substantial increase from where we were modeling in our own plans. But with the reauthorization, another third one, right, could potentially bring us, you know, 500 to 600 total to the balance sheet. It's a pretty big deal without any dilution. I think that puts us in good place from where we started the year with the quarter, we had 534. If you add that on top of the gains in revenue, it puts us in a very good position to maintain an adequate balance sheet and hit profitability in the time frame we're looking at with additional cost controls we've put into place.

Operator

All right, maybe just digging into Angelman ahead of the phase three data in the second half as you laid out. So what do you need to see from the primary endpoint of Bailey-4 cognition in order to see a successful study, and then what are the kind of key risks here?

Emil Kakkis, CEO

Well, we have looked at the modeling of the power of that endpoint before. The data we just put out in Phase 2 suggests that at 12 months we could see somewhere close to 10 points of improvement. I think we modeled a smaller number than that. But with the standard deviation we saw, we were seeing 80%, 90% power or greater, depending on what you assume for the control group. If you assume what we see in natural history or in studies, then we have 90-plus percent power. If you assume the background could be two to three times higher, a little bit less than that. But the history of control groups, whether it's the Levodopa trial or the natural history study, they really haven't gained more than a point on Bayley. And so we feel pretty comfortable that there isn't going to be a big placebo effect going on there. And therefore, you know, I think we're well above 90% power to detect the magnitude of change we're seeing. So I think we're in a good place. So we've put out a little more data on this power before, but we feel comfortable with the strength of the study. That said, it is neurology. Neurology is always hard, and there's always things that go wrong or things that go off. We have to be conscious of that. And we put in the multi-main responder index for two reasons. One, it's a more powerful assessment of all the domains that are affected and I think a better alignment of what patients are thinking. They're not thinking about one endpoint. None of us think about any disease we have as one endpoint. We all think of multiple problems, right? And so the MDRI is a better line than what patients think about what are the big five issues that affect their kid. But also, importantly, it's a very powerful analysis tool and gives us more power. So if there were any problems with Bayley, the MDRI is more powerful and will capture more endpoints which help balance out if there's any risk. We're allocating 20% power to the MDRI, 80% to the Bailey. 20% is enough for the MDRI to be successful. It doesn't need very much power. We expect it to be able to beat that level readily. So that's how we've designed it. We hope that it will help put us in a better position to win one way or the other. And if one or the other is positive, we believe we'll still be able to file for approval with that. We expect both to be positive.

Operator

All right. And then I guess maybe just taking a step back, Could you just talk to the rationale for choosing the primary endpoint of Bailey-4 cognition as opposed to receptive communication, which is what IONIS has selected for their Phase III study?

Emil Kakkis, CEO

Yeah, I think they picked expressive, probably.

Operator

Yeah, expressive communication.

Emil Kakkis, CEO

I think their argument was that expressive communication is what parents want, but I would argue I don't think parents want their kids to start talking but not having any thinking. That may be what's happening already for us with teenagers. but, sorry, bad joke, but the, there's no one here to laugh anyways, but, so, you can't have anything without cognition, so the idea that parents want it, well, I think that the, if you look at the cognitionists at the core, we think it's the most fundamental function, FDA has expected it, but I would say to you, we're evaluating all the other endpoints as well, we can look at all of them. We'll look at expressive. We'll look at receptive. But expressive does take time to evolve, and it also can be dependent a little bit on how much training or education. I think it would probably work better if you're doing more work on educating kids to help them develop their language skills. But, you know, I think all of these things are important. So we picked Bailey for it as being a more fundamental function. There's also history. We're also being using it in the sample evil program. It's something FDA neurology is familiar with. So those are some factors. But I would not look at it as defining what's most important in the disease. It's what we need for a regulatory process. But what patients will see is that endpoint, secondary endpoint, end-rider. They'll see the whole thing. And I think patients can understand endpoints. Whether they're primary or secondary, honestly, does not really matter to patients. They want to know what's happening. and they're not going to pay attention to the regulatory rubric of statistical plans.

Operator

You touched on this briefly already, but just given the one-point improvement seen in natural history historically and then the 10-point improvement that you saw in the phase 1-2, I guess what's your level of confidence that the sham control arm in the ASPIRE study will not exhibit a significant placebo effect that could kind of compress the treatment effect size?

Emil Kakkis, CEO

Well, the main reason is the type of endpoint it is. and the type of patient we're dealing with. The ancient patients will be gaining function, but they don't necessarily have the understanding they're in a trial. Like, they don't really know what's going on. So the placebo effect depends on you knowing something and having some belief in something. That's not really going to happen. Now, we exclude all caregiver input, where the caregiver could have that placebo effect. No, they know. But that's being excluded. So we think that will help. The other thing is that this is assessed by a third-party psychologist, not the parent, not the doctor, third party. So the value of that is they're more objective. They're not connected to the family. They don't know the family. They're just doing the testing. Does that make sense? So they're, I think, going to be a little bit more objective in their professional design. So those are the things they're doing to help control for it. But if you look at the randomized placebo-controlled trials that have been done with Angelman, which is the one levodopa trial, for example, that was placebo-controlled, there was no Bailey placebo effect observed. So that's not a natural history study, an actual trial. It didn't occur in that study.

Operator

That's helpful. Maybe just quickly on safety. In the Phase I-II study, there were some cases of lower extremity weakness. Do you believe that these have been mitigated via the use of the Trendelenburg flush in the Phase III?

Emil Kakkis, CEO

Yes, we believe it has been alleviated. I think the issue we're having based on the MRIs and everything else is pretty clear that there was local concentration of drugs that was causing local chemical irritation. As long as the patients are put in a tumor and the drug is driven cranially to allow for rapid mixing, we seem to have eliminated that, and so we feel pretty comfortable. And we have patients now for five years on drugs, up to five years, not having a problem. So if it was really a chemical, it was a drug-related effect, it would have, it should have either accumulated or occurred, but I think it was very much an administration-localized effect. And I think we've managed it through these changes.

Operator

And as you mentioned, you're also running the Aurora study in additional age groups and non-deletion genotypes. Can you talk about the regulatory filing strategy once you have this data in hand? And then also your level of confidence in that data set, given this is a more heterogeneous population.

Emil Kakkis, CEO

Yeah, so the Aurora study will help broaden the label of past deletion, as you mentioned. It includes missense, UPD, ICD-type patients. It also includes under age 4 and over age 18. And so the idea is here to cover the rest of the... we haven't put forth what our filing strategy was going to be. We'll have our phase three data. We'll have Aurora data and we'll come up with our exact planning, but the four to 17 age group deletion, we think is the majority of the market are in that range and so forth. There are going to be some adult with age when we'll get to them, but what we do for the filing right now is still left to be finally decided. But we think it's most important to get the major market. And the Aurora study will give us knowledge about the rest of it.

Operator

And if that study is not stat-sig but shows a trend, do you think that would be enough to get that, you know, the broader label?

Emil Kakkis, CEO

Well, I think that it depends a little bit on what we're seeing. We are looking at MDRI in that study, by the way, in those endpoints. and it's pretty powerful. So when we had even 12 or 13 patients before and after comparison MDRI, we saw strong statistical significance. So it's pretty powerful with that tool,

Operator

not just a single endpoint.

Emil Kakkis, CEO

We are looking at Bayley and the really young ones, of course, but I think the methodology will make it a little better for us. Now MDRI, you might say, well, it's not blinded. How does that hurt you? But the value of MDRI in an unblinded situation or open label is that you don't count anything unless it's a really big change, right? If it's a little change, like a little bias, you're not sure, that won't count. You have to have a big change. So the MKI has a natural filter for small changes. The only thing that counts are big changes. So if they get better, they're getting better in a big way, I think you can be more confident that that is something real, right, as opposed to something that's just bias on how they're using the tool. So those are some features. I think it will be enough. I think in the past it hasn't been enough. In CRISFIDA, for example, when we originally filed that program, we had our trials were in the 5 to 12, and there was this older patient trial, but we didn't have any under age 5. But we submitted four patients with data under age 5, four total. We had 13 who had been treated, but four with six months of data. But we were able to extend the label with the X on 5 to 12 data and with supportive data just for patients for six months, and we were extending the label down to age one in that filing. So it was open-label, supportive, extending the data to an age group. So we've recently done that very thing and was successful, and it was really only four patients. But the four looked very good. They fit. The safety looked fine. The 13 got doses. Drug worked the same. So I do believe that it has to look good in those patients. If it's not distinctive, clear that it's working, then maybe it won't work, but it will work if it works the same it has been working and does well on the MDRIs, I think we'll be pretty confident that we can put that forth and allow the adaptation. We specifically decided not to put patients through another randomized control trial because to put all these subtypes, all these smaller subtypes, into randomized trials for each type would have created a lot of cost and put a lot of burden. So we put the burden on a group of kids from 4 to 17 to prove cause and effect of this drug. And for those kids, we just show the effect again. We don't have to prove the relationship because we've already proven that this is a cause and effect relationship. Does that make sense? And now we just need to prove that they have the effect and they have safety.

Operator

Maybe we'll pivot to the upcoming gene therapy launches, the first of which is in the next couple of months, potentially. Could you just talk to the early launch dynamics for both of those, both GSD1A and then Sanfilippo syndrome type A, including maybe pricing and then also which patients you think will be early adopters here?

Emil Kakkis, CEO

Yes. And so, first of all, of course, assume that we get approved. So, I appreciate your optimism to talk about launch and launch dynamics. We always have to give the FDA a due that they have something to say for us before we launch. We feel like review is going fine, but we'll see. We'll get done. Now, the launch dynamic for the two are probably similar. I think for Sanfilippo, it's probably the easiest one to talk about. Sanfilippo syndrome is a horrible neurodegenerative disorder, and kids are losing brain cells every week that they wait. They have no other treatment, and between the age of two and six, They lose a lot of their developmental function. By 10 years old, they're bedridden, and they may stay in a bedridden phase with G-tubes in and out of the hospital, non-responsive for 5 or 10 years. So it's an absolute horrible situation. There is no parent in that situation that will not want to get treated as soon as possible, even if they're 5 or 6, because we've had patients in that age range who may have lost speech already but are walking, feeding themselves, interacting with the family, who have stabilized. And we've shown five patients that were older that stabilized their function, and they continue to participate with their family and continue to self-feed, walk, and so forth. So we think that therapy can work in that group, but the younger the patient, the better outcome, and we think there will be great urgency not to wait. The longer you wait, the less. So we think that one will, dynamic, will be urgent, and once approved, there'll be people clamoring to get treated promptly. We're hearing about patients now that are very active on social media, but we're also getting inquiries from Europe about named patient treatment, and the Middle East as So we think there's a lot of interest in the first-ever treatment for a neurodegenerative I think it's a pretty easy call. and the treatment is a relatively safe 3E13 infusion dose. So it's not a very high dose. We don't have the kind of complex safety issues that we've seen with some of the others. So there's really the downside effects, I think, are modest compared to the potential benefit. So that's the dynamic for sample leaf. But for GST1A, it's an urgent disease. It's not like your brain is going. You can survive on cornstarch treatment, keep yourself, but it is not a great survival. It is a difficult life because you're taking starch every few hours, all day, all night, about a pound of starch a day. I don't know if you can imagine eating a pound of starch with flurry. It makes you sick thinking about it, right? Well, they feel sick doing it, by the way. They do not feel good. They're all like induced type 2 diabetics. So imagine you're making yourself sick, but you have to keep doing it because you're trying to avoid running low, and you don't know when you're going to run low. So it's like the opposite of diabetes. You're trying to keep your sugar up, but you have the worst problem is that the drugs don't, the starch doesn't last very long, so you have to keep taking it, keep taking it. And if you don't wake up at night, you could end up with a very low glucose, comatose, or not wake up or die. That is a scary thing to live with. So there is a substantial urgency, and when we were rolling this trial, we had people want to get in, you know. and we even had a problem in one country that they didn't review it very quickly and we enrolled before this country got started. We canceled enrollment. Parents, patients were so upset. They called the regulators who called us and demanded we open the trial to let their kids in. And we couldn't do it. We'd spent all the slots. But it tells you something. I've never had a regulator call us, demand that we open a trial in their country. I've never had that happen, right? That's how intense the feeling was. So I know there's urgency. If you deal with a problem every single day, every few hours, you think about that. And you have to know that if I don't drink the starch, I have a gun to my head, and it might go off if I forget to do it. Just think about that stress of feeling that way. You want to get off that if you can. So we think GSD1 will do well. There's more patients with GSD1 in the PREP and the population than in San Felipe, although they have similar maybe incidents, but the prevalence is maybe 1,500 or more in the U.S. For GST-1A and for San Filippo, there's maybe 300 or 400 patients around in the United States. But the urgency is very high. We think both programs will do well. We think we feel good about the potential for those programs to achieve meaningful revenue for us. They may not be like other programs, but if approved, we think they will be successful gene therapy products and, I think, be supportive of the whole field of AAV gene therapy.

Operator

I guess maybe just in same tempo, given there is no standard of care currently, how do you think about patient identification and whether there might be a headwind there trying to find those patients?

Emil Kakkis, CEO

Well, I think the challenge is finding them early enough to have the best benefit. The truth is you really need newborn screening to capture patients early because you really want one mother age, too. The methodology for numerate screening is the same methodology. They already have approved for MPS1 and MPS2, which are being implemented in numerate screening. So MPS3A is comparable, and there's a method. So it's not hard to implement. It could be implemented. It should be, but the numerate screening control system, the Secretary's committee is not operating. So we have to work through the Secretary Kennedy to help bring forth the need to start newborn screening. In the meantime, what we're looking at is to help support and make sure that patients are being included in panels for developmental delay or other early signs that you would express in San Felipe. Some patients are getting diagnosed earlier because of that, that any kind of developmental delay is being evaluated. but we need to get infant and newborn screening done, make sure panels are being used for those early developmental day patients and then use our network connection among the interborne area doctors to make sure that we're finding many as we can but I agree with you, it's one of the pieces right now I've said we've found about 300 to 400 patients with Saint-Philippe already found in the United States and we know the age ranges etc of the patients out there will all patients get treated? Later stage patients, maybe not. If they're very advanced, not responsive, parent may decide that it's not right, and we don't know what the label will do. We've treated people up to age eight or nine in the trial, so that range could be readily expected in the label. Whether it'll go beyond that, we couldn't be sure. I think patients are still ambulating and probably a range that makes sense. We'll have to negotiate what the labeling shows, But among the patients we've found, I think that will keep us busy enough with supply for the time being.

Operator

I guess on that note, could you just speak to the capacity at your Bedford manufacturing plant and whether you have capacity to meet the expected demand for the first maybe 12 months of launch?

Emil Kakkis, CEO

Well, because unfortunately or unfortunately because of the delay, we've been accumulating more commercial products. So while the launch last year would have been more supply constrained where our supply is continuing to increase and been running continuously, the drug substance is actually made at a contract manufacturer in Ohio, and we do the fill finish at Bedford for the sample EPO program. So that program is continuing to run continuously and build a supply, and we think we should have plenty of supply to handle the demand based on what we think we need for the first 12 months. For GST1A, we're doing both drug subs and drug product. Again, we should have enough supply to handle the need. Of course, there are more prevalent patients with that disease, but we have enough for what we expect to be the population that would get treated in that time frame.

Operator

Maybe just on commercial efforts, I think you've mentioned before that you plan to leverage the existing MEP-SEVI and DeJolvi sales force. But given that these are gene therapy launches, could you just speak to the investments being made to manage the high-touch requirements of a gene therapy launch and the long-term patient monitoring that's required?

Emil Kakkis, CEO

Well, there's several things we're doing. from the patient services side we're creating a gene therapy guide it's one of our patient services group that become point for helping coordinate all the different functions that are going on we've created a separate group with the gene therapy treatment group which is physician experts who are going to guide qualified treatment centers on both treatment and and immune modulation or co-medication management so that they have an expert at hand at all times to help them. Our commercial team is also creating the qualified treatment centers who will be prospectively trained and ready to go at launch. And so those things, there's a few extra people that are in the gene therapy treatment group. There's been some support for the MSLs required, and the patient services group will be sat with some specialized people to help handle the unique needs. So there are a few places we need to bolster. on top of the existing commercial group to manage specifically a gene therapy. The supply chain is also a bit different, and so it's following QA because we're going to be, we have flat pricings expected, so that means every group of weights is its own code and has to be packed. So you actually have to create a supply chain that can handle creating a product for each patient's weight in real time. so there's some people in the quality supply chain people that have to be able to do that the idea is that we will have flat pricing for the gene therapy across the age groups so there is some logistics involved in doing that so there's some place we have to do but it's not a big lift not as big a lift as getting here

Operator

maybe just for the last few minutes anything else you'd like to highlight from the pipeline and then also if you could just quickly touch on citruzumab, and whether you've completed those additional analyses of the Phase III data and whether there's a path forward potentially in some subgroups or age ranges.

Emil Kakkis, CEO

Well, we've done quite a bit of analysis. We talked about some of it at J.P. Moore in the pediatric subs group. We certainly see excellent improvement in formality, really, in everyone, but we saw improvements in pain, physical function, vertebral fractures, certain other areas. So we've done a lot of analyses on that. I think we wanted to do it carefully and thoroughly, and there will be discussions with regulators around pathway. We'll probably put out information on what that pathway is later in the year before we come up with Angelman data. Somewhere in that time frame, we should have some understanding. So when we made a decision, what we're doing, we'll know then. The goal is to try to find a way with existing patients and ongoing treatment to be able to come up with a path to filing. We can always do another randomized trial. We're trying to avoid that, which is a multi-year kind of a thing. We have a lot of data. We have two randomized trials and other patients ongoing treated. So we hope we can work with regulators and coming up with an idea. We think the drug is working, but of course we didn't hit the primary and secondary fracturing points. So that's a factor that will always be an issue for us to solve.

Operator

Anything else from the pipeline that you'd like to touch on?

Emil Kakkis, CEO

Well, we've been incredibly productive. We have OTC phase three that was paused. It'll be ongoing. We have Wilson cohort four coming. Those are in play. But we also have some things we've held back. And if we hit our marks on our gene therapy approvals and launches, we have a program for creatine transport efficiency we've had for a while. It's a pro-drug of creatine, a really cool drug that we've made ourselves. It's actually a ring, a ring pro-drug. It has two clips, but we can deliver creatine to the brain very efficiently. And that's a very large market disease, maybe 30, maybe 50,000 patients. No treatment at all. Males and females both have infected symptoms that could come to the clinic. And we're having some support from the patient group moving that forward. We also have a gene therapy for CDKL5 deficiency. You might think another gene therapy. There's a neurodisease, intractable seizures. It's like what used to be called atypical Rett syndrome. So like Rett, we expect it could have dramatic effects. They're propelling the Rett programs forward. We think it's another good one. I just want to be clear, we're an engine of innovation. We have an incredible number of products we put, and those INDs have been sitting and waiting for the opportunity. So we need to create the value, get the value, and drive forward and put some of these programs in play and show that we can be the most productive rare disease company in the business.

Operator

All right, with that, thank you so much for joining us.