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

Good morning, everyone. My name is Gena Wang, and I'm [indiscernible] analyst at the Barclays. Welcome to our seventh Gene Editing Gene Therapy Summit Conference. I would like to thank all the participants, investors, companies and especially our event team and corporate access team who made this event possible. With that, I would like to introduce our next presenters, Eric Crombez, Chief Medical Officer, Gene Therapy from Ultragenyx. Eric, thank you very much for joining us today.

Right. Great to be here.

Yes. So I know last week, we just had the ASGCT, you present quite some update last week. So maybe I would just start with a question on your several gene therapy programs. First one is the DTX401 and GSDIa, so when we look at the ASGCT update a longer follow-up, certainly very clear supported durability. However, when we look at the different cohorts, it seems there is no clear separation in terms of a cornstarch reduction from different cohorts. And that do you now from the hindsight, do you think you still have optimal dose and a sterile regimen for Phase II/III?

Yes. No, absolutely. And for our GSDIa program, we're in a traditional Phase III now, and that study has been fully enrolled. And cornstarch is our primary endpoint there. So very focused on reduction of cornstarch in that study. It is a double-blind, placebo-controlled trial. So that's why we're really still looking at the Phase I/II data for our external publications and was a presentation at ASGCT. And I think it's important. It's important to continue to look at this long-term data because a big part of this and a big part of dose selection was durability. And I think when we were initially looking out at the readout from the Phase I/II study going into end of Phase II with the FDA and other regulatory meetings, you have a rather fairly limited insight into durability there. So I think when going to the different dosing cohorts, I think what's great is you're seeing compelling results at all doses. And while cornstarch remains our primary endpoint, we are really looking at the totality of the data available to us. That's total cornstarch amount, frequency of cornstarch, time to hypoglycemia. And also very importantly, we do this as part of the formal part of the study with interviews is the more subjective part of this, the stuff that sometimes is a little bit harder to measure -- how these patients are feeling. It's a disorder of energy metabolism. So we have a lot of patients who are really reporting a lot more energy, the ability to exercise travel some patients going back to work, and that was very important. So looking at the totality of the data, we do think that the dose we brought into the Phase III, roughly 1e13 is a rate dose. And I also think looking wholly at all of the available data for liver-directed gene therapy, I think that e13 range really is that rate correct range where you're really balancing efficacy and safety.

Eric, can you remind us the steroid regimen?

Yes. So we evolved our approach with steroids. So certainly, we've been using steroids for a long time, I think, well over 10 years at this point with those initial studies in hemophilia. I will say when we brought our initial programs in the inborn errors of metabolism, GSDIa and OTC, that reactive steroid approach, waiting to see if you had an increase in LFT, then starting steroids and trying to control that response was really what was done, and that's what we started with. We evolved our approach, and I think it's fair to say that it continues to evolve with us and more broadly, towards the prophylactic use of steroids. I think that does help. I do think we can do better on the immunologic front. I think controlling that immune response is important. I do think it drives a lot of variability in all of our gene therapy programs, at least a peripherally administered ones. So we're bringing forward prophylactic steroids in our pivotal trials, but we are thinking quite a bit about moving beyond that and really looking at other B cell and T cell depleting drugs.

I see. Okay. Very good. And then I don't know if you can share like what is the powering assumption for the Phase III?

For GSDIa, we are stratified by age. We're looking at pediatric patients separately from adult patients. The growth does come into play activity levels, puberty. So we reduced stratified by age and then also target blood glucose levels, really how often patients are in range versus out of range really that focus on hypoglycemia. So that is how we're randomizing with the 50 subjects we're enrolling -- plan to enroll in the Phase III study. I think fair to say that if we see the results we saw in the Phase I/II, we're very well powered to be successful with this Phase III study.

Okay. So which means 60% to 70% cornstarch reduction at 48 weeks, right? That's what we're seeing from the Phase I/II. So that will be sufficient.

Yes -- obviously had those conversations. We had a lot of conversations with the FDA and other regulatory agencies, and we have agreement that reduction in cornstarch is clinically meaningful.

And then from -- I'm pretty sure you also talked to a lot of the physicians as well, like what would they be looking for regarding the cornstarch reduction that will be considered clinically meaningful?

Yes. And I think that's important. And I think oftentimes, you're kind of push to picking a number, and I think that's hard because you do see a lot of variability. And again, yes, it's important that reduction on cornstarch is our primary end point, and that drives a lot of this, but that's not really the totality of what we're trying to accomplish with this drug. So again, we're really looking at how these patients -- how we're really establishing normal glucose metabolisms for the first time here. And we do understand also these patients have not been able to break down glycogen to produce glucose during times of fasting or metabolic stress ever. So it takes time to establish normal metabolic pathways. So we think that's great progress. We see great results early on and then a lot of durability going into the out years, but we really are focused on how these patients are doing overall and not just reduction in cornstarch.

Okay. Okay. The -- so the other part, when we look at the second -- or like the data package that you plan to submit to the FDA. You also said we like to have a long-term Phase I/II data as a supporting durability and approval. So what kind of long-term follow-up data? Like is there any particular, say, number of years follow-up you need to have? And also, is there any percentage of cornstarch reduction that FDA is looking for, for the long term in order to deem that could be supportive?

Yes. So our primary efficacy analysis period for the Phase III is 48 weeks. I think anytime you're going to talk to any regulatory agency, including the FDA, I think their bias is always for a longer-term follow-up and more data. And I get that we do think we see very compelling results within that first 48 weeks. So it is the data package we intend to submit for approval. But that means that's 48 weeks for the last patient dose in the study. So certainly, for the patients enrolling early in the study, we will have longer-term data, and we will submit. And then we will have, obviously, 4, 5, 6 years plus for data from the Phase I/II study. So I think in the totality, we will have a very good idea of durability. We had quite a few patients dose in our Phase I/II at the dose we took into our Phase III. So I think as long as durability is holding up, and I think it's fair to say with the data we presented at ASGCT, we're seeing good durability. I think that should be sufficient. In general, though, we want -- sorry, go ahead.

Sorry.

Yes. I think durability is important for us beyond what we're -- the conversations we're having with regulatory agents because to me, whether even if it's 10, 15, 20 years down the line, these patients, if there is dilution of the transgene due to growth in pediatric age ranges, hepatocyte turnover. We do need to monitor them and understand that and make sure they're not at risk for very significant hypoglycemic event. So our intention is to follow them for the long term beyond the commitments we make to regulatory agencies.

Okay. That makes sense. Your second program, the DTX301 and OTC deficiency. Also, the ASGCT update Phase I/II also support durability now with up to 5.5 year follow-up and then the rate of responders and the complete responders were maintained. So now when we look at the -- I think the primary endpoint is a complete responder. That's like 4 out of 11 when we saw the Phase I/II data. So the -- maybe also again asking from did the FDA set a minimal threshold for the rate that they were looking for? There's one question is approvability for the rate. And the second is the again asking from the doctor perspective clinical meaningful. What is the rate for clinical meaningful perspective?

Yes. So again, and I think that's great. Great work we did with the FDA and other agencies because we weren't really forced to set that threshold. We didn't see a threshold, and we are looking at kind of an overall responder rate. So that's the responders plus the complete responders overall. And then we will look at complete responders, those patients who have -- who are able to completely discontinue alternate pathway medication and come off of their protein-restricted diet versus responders that can decrease that by half. And so we put that in an overall response category for the primary endpoint and then break it down in the secondary -- the second primary endpoint is also important, and that's maintaining ammonia control. Ammonia control was used as the basis of approval for some of the other alternate pathway medication. So that is a clinical endpoint at this point. So again, we are looking for approval, not a biomarker likely to predict. So we think it's important there. We are looking at non-inferiority just because you do need to control these patients' ammonia levels and you can do that during times of good health when these patients are under good metabolic control. The problem we see with current standard of care is that they're still having metabolic crisis. They're still having quite a bit of neurocognitive damage. And we think by replacing the missing enzyme with the use of this transgene that's the best way to prevent metabolic crisis in the future is by establishing a normal function of the urea cycle. So again, with power, we are stratifying by gender if this is an ex-link disorder and then also ammonia control because even with the best care, the best use of alternate pathway medication, you can't always control ammonia levels. So that's our stratification. And then again, similarly to GSDIa, if our results from at least -- from the Phase I/II study are consistent for the Phase III. We have a -- we will have a successful Phase III study.