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

It should be similar to what we did with Crysvita. We also talked about the number of doctors that are prescribing. I think it's useful to understand the breadth of prescribing across the country. The number of start forms, the number of reimbursed patients who are on reimbursed therapy, that's what I would expect to be seeing. It should be enough of the early indicators for The Street to understand how the launch is going.

Okay. So then moving to your gene therapy programs for both DTX301 and DTX401. You have end-of-Phase II meetings with the FDA by year-end. Have you had those meetings yet? And if so, what is the feedback then? And has there been any areas of pushback?

Well, we generally don't sort of advertise the timing of our meetings. What we will do is when we have the meetings and we get resolution with the agency regarding what the Phase III plan is, we'll put out an update to The Street on that. So we'll do that as soon as we kind of have that resolution. So we haven't put that forth yet. The FDA and CBER particularly is very, very busy with regard to COVID vaccine work. I'm sure you've been seeing some of the news about that. That is creating some challenges at getting meetings with the agency. And I think that the team at FDA is working hard to keep up with all of the COVID vaccine work and doing their best, but a lot of gene therapy programs are a bit caught in that process right now. But we expect to have our insight on what to do for both programs before the end of the year. And our basic strategy is not unusual or difficult. They're randomized controlled studies, which are quite solid and basic and of a size that are in line with a lot of other programs and are using endpoints that are, I think, relatively direct to the disease cause or have been used before like in the OTC situation. So we don't think that the trial design or endpoints is there's -- that there's any particular risk there. But we do need to get it crafted in detail with them and an agreement put forth, and we expect to have that before the end of the year.

Well, that leads right into my next question, which was just about how much time you would need after you got feedback from the FDA to plan your Phase III for DTX401. You had guided to early 2021 launch. So you're comfortable with that even with a potential later FDA meeting?

Well, it's constantly being monitored. It's usually a few months from FDA feedback, final protocol to get 2 sites set up and the first patient in. It's usually in a few month time frame. It can vary. It depends how -- which countries and how we're going. We're going to work on doing it as promptly as possible, but it should take a few months between having our final agreement and moving forward. We're also clearing the European authorities as well on input to the program. So that will be another piece of the information that we'll want to incorporate in our plan.

Okay. And then for the DTX301, data from cohort 4 are expected by year-end. How many of the 3 patients have been dosed?

We haven't provided an update. The sites have opened, and therefore, the process has begun. And we still feel we'll have data on those patients before the end of the year. Our main goal is to try to assure that treating prophylactically steroids is safe, both for ourselves and the regulators. And we will get some efficacy information, but it was mainly determined with this -- this easier way of treating with steroids would be an acceptable one for OTC and be safe. We hope it may improve potency as well, but the main thing is to just show that this approach will be safe and appropriate for Phase III. And our general habit is to try to test things like this before Phase III rather than doing it for the first time in a blinded study.

So how critical are those results given that you're already planning to incorporate the prophylaxis into the Phase III? And what kind of things could you see in the data that might impact the Phase III?

Well, since we've been treating all the patients with steroids at some point and some with our current strategy fairly early on, I don't think that it should be that different. The probability of having something unusual, I would say, is very low. But with Phase III trials, you want to have as little risk as possible when you enter the study. So we're planning to do prophylactic steroids. We think it's the right thing to do for OTC, and we're comfortable that it's safe. So this is really just a confirmation of what we think we know. And everything we write about and plan with the agency will include prophylactic steroids is the way to go for this disease.

Okay. And for DTX401, you've previously said that one of the goals was to increase the time to hypoglycemia to around 8 hours so the patients could sleep through the night. You've seen improvements in time to hypoglycemia and strong reductions in the cornstarch, but several of the patients still haven't gotten near the 8 hours. So what's your latest thinking about that? And which endpoints are most meaningful to you now?

Well, first of all, time to hypoglycemia and getting throughout the night is still important, and it's not changed. What we're seeing, though, is that a lot of the patients are hyperinsulinemic as they make too much insulin even when their glucoses are low. And it could be because they've had years, some of them decades, of oral cornstarch every 3 hours. That will crank up your beta cells and produce a lot of insulin all the time. And we're seeing that they have -- they just make too much insulin. So as we look at the patients who were treated early on in the study who are now out at a year or later, we're actually seeing their hormonal balances kind of settling down more. And we've also noted in the second 6 months, if you look at the continuous glucose monitoring, we can show that the patients are actually going through the night fine, and they're turning the corner and maintaining their glucose and not dropping even though they're not getting starch in the middle of the night. So we feel comfortable that the efficacy we're seeing is sufficient to get patients off the need for any cornstarch and particularly cornstarch in the middle of the night. And so it's just a question of running an assay early in a program before the physiology of the patient has fully adapted. Because of that, we're discovering the fact that they get hypoglycemic really easily with the starch, causing hypoglycemic reaction. And so the whole continuous glucose monitoring has allowed us to be more responsive to the patient situation and bring their starch down and to be more -- titrate carefully. But as a brain comes down, then they start -- the body starts to adapt and then we can lower it more and lower it more. And as you see the data as we go out over time, it continues to fall and the patient's physiology starts to normalize. So we're encouraged how it plays out long term. I think it's just about taking a patient who's had a certain physiology for years, sometimes decades, and training it into a new regime, a more normal regime where their liver makes the glucose. They need -- not by taking orally.

Sure. So maybe in the last minute, let's talk about your earlier-stage program. So you're planning to submit the IND for UX701 by year-end. Is that still the case? And is there anything beyond completing the application that remains outstanding? And what excites you about the program?

Well, we're still on track. There are certainly many things that could slow us down because of COVID. There are analytical labs, for example, they have to operate. If someone gets COVID in a lab and everyone gets sent home for 2 weeks, then suddenly the lab is not executing on its time line. So there are a lot of things like that, that could cause us a delay. So far, it's gone on track. We've done the GMP manufacturing run. It has gone well. We feel finished, and we're in the process of testing and releasing the product that would be used for the trial. And that HeLa platform that we're using has produced a lot of products, so it was excellent. And we're very pleased with how the supply will go for that program. The clinical part, we've been discussing with authorities. And I think there is -- because of a precedent in treating Wilson using chelators, there's some knowledge about endpoints and biomarkers that can be used, which makes this a reason that we can go a bit faster. And we believe we'll get to agreement on those endpoints relatively straightforward -- through a straightforward process with the agency. So those items are all on path. Barring any other delays, we should be able to make the IND at the end of the year. And we're continuing to prepare with sites and CROs to get set to run the trial. It will be a significantly sized trial, and we are looking to move rapidly through the dose cohorts, establish the dose and then move into a randomized controlled format.

Great. And can you give us an idea of the market opportunity with Wilsons and what the unmet need is and standard of care is currently?

Well, there's more than 50,000 Wilson patients, and I'm guessing there's still a fair number undiagnosed because it can look like a lot of diseases. It's very complex in how it can present. So at least 50,000 patients. So I would say it's around 10x larger, for example, than some of the other disease we're working on, almost 10x larger than the other 2 gene therapies we're working on. So it's quite large. The current standard of care is chelator therapies. There are some old ones that have a lot of side effects that are hard to tolerate, but they do reduce the amount of free copper and can help protect the patients. But there are still many [ patients ] who progress who still continue to have worsening liver injury and CNS complications from the excess copper. And even with a chelator, it doesn't restore normal copper distribution, to be clear. It gets rid of the excess free copper that's oozing out of your liver that's full of copper, but it doesn't really clear the copper from the liver, and it doesn't put copper in the right ceruloplasmin-bound form that your body needs to use copper. The gene therapy, unlike the chelators, will restore both the detoxification of copper and the removal from liver, but it will also restore normal copper delivery through ceruloplasmin. This is why we think gene therapy could be a substantially better therapy than chelators. What I would say is initially, the most significantly affected patients will likely be the earlier adopters for the gene therapy. But I think over time that -- our expectation is that a significant fraction of the patients will want to get a permanent treatment if we can develop the safety and efficacy data to show that it works. We're encouraged by what we see in the mouse model. But within 4 weeks, we can reverse liver inflammation and disease and change copper and raise ceruloplasmin levels. So if we can achieve anything close to that, I think we'll have an important therapy for Wilson disease.

Great. So for GTX-102, preliminary Phase I data are expected in the first half of next year. Previously, you've said that the first 2 cohorts were enrolled with patients receiving multiple doses. Can you provide an update on that study? And what should we expect to see in the initial data next year?

Yes. So we've treated a few patients in the first cohort, and we're continuing to look at the safety and efficacy in the program. Our expectation is to provide an update early in the year, and we wouldn't do that interim. Our goal is to try to provide the data in a more organized way as opposed to a patient-by-patient way. We're encouraged with what we see, and we are hopeful that Angelman will be a disease that can be reversed through a highly specific genetic therapy. And the science behind it, I think, are very good. And the work that Scott Dindot did with the genetics team, I think, is exemplary. And with that insight, the possibility of turning on a gene in the human brain and restoring neurologic function is really there. And we're encouraged by the prospect of taking disease with more than 60,000 patients and actually changing the future for them. So we're excited about the potential, and we're still continuing to look at the safety and efficacy of the product.

So you mentioned the 60,000 patients. What is the unmet need within all those patients? And is there a certain subset of those patients that you think would be best for this therapy?

About 70% of the patients with Angelman have a deletion and tend to be the more severe type with multiple domains impacted. But even the point mutation patients and some of the others do have significant disease. I would say all the patients are potential addressable patients. And I would not say there's any patients that are too mild to consider treatment. I think they're all significant enough. But there is some level of severity spectrum. But the deletion patients make up the majority of the population. So we do think the majority of that population is potentially addressable with the treatment.

Okay. And then maybe for our last question, what do you think The Street misunderstands or underappreciates about the Ultragenyx story?

I think they underappreciate our ability to find and develop assets efficiently or with average time from IND to approval of just over 5 years, 2 years faster than any other company. We've also been picking and developing a wide variety of modes, which makes us a more robust company. Our gene therapy franchise is not fully appreciated, but we will have, by next year, probably one of the most diverse gene therapy franchise out there, including the large pharma. And I think our HeLa platform is going to be the way forward for AAV manufacturer that's cost efficient and viable in large-scale diseases as well as rare diseases. So the franchise there, I think, is not appreciated. But as a company, we've been building a pipeline, I think, that's better than any out there. And our ability to navigate clinical development, regulatory and now commercial as well, I think, sets us aside as a premier rare disease company.

Great. It looks like we'll have to leave it there. Thank you so much for your time.

Thanks for having me, Hannah.

Of course.