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

Okay. Well, thank you, everyone. My name is Gena Wang. I'm a SMid cap biotech analyst at Barclays. It is my great pleasure to introduce our next presenting company, Ultragenyx. On the screen with me is Emil Kakkis, President and Chief Executive Officer and a Co-Founder of the company. Emil, I will hand it over to you.

Well, thank you, Gena. Thank you for having us on the call today. Happy to be -- give you a brief update on Ultragenyx for just a couple of minutes, and then we can go into any questions you may have. It's been a remarkable year for Ultragenyx as a company. It's our tenth year since founding. And in that year, we completed 2 product approvals for Dojolvi and the TIO indication for Crysvita. We continue to manage the significant launch of both products that we were approved and now the 2 products and despite the COVID situation. We attribute it to our field teams and the whole company really to get those approvals and continue to launch well. The gene therapy franchise, I think, has been built out with 2 programs heading to Phase III and a third now entering a single pivotal-type design for Wilson disease. We added onto that with the Solid deal to work on Duchenne, which would take advantage of our P -- HeLa platform technology which allow us to produce high-titer vectors in very reasonable cost. We also managed to leverage that platform for a deal with Daiichi Sankyo earlier in the year. Now I add onto that, the opportunistic deal we did last year to work on [indiscernible] for Angelman syndrome and exciting data we released earlier regarding the substantial improvement in Clinical Global Impression scale for Angelman syndrome for 5 patients with at least 2 of the domains that were much improved or very much improved with an average CGI score of 2.4. There is a safety event from lower extremity weakness that comes on and resolved. We believe this event can be managed through dose and administration changes, and we look forward to getting back in the clinic again and treating those patients. But we're excited about the possibility that you can actually change the developmental status of patients with Angelman syndrome, which until this data came out was not really known, was only in theory. Putting that together, we also have other early pipeline that's coming to progression. And then we're continuing to do business development, being -- looking for smart opportunities, particularly in building out our bone and metabolic franchise to follow on our Crysvita program. We are very excited about the future. I think from a cash perspective, we raised substantial cash in November, which puts us in a great cash position, allowing us to fund and do what we have to do going forward. As a company, we're going to build the pipeline, but we're also completely cognizant of the need to move toward profitability and to manage those 2 in a way that's intelligent, that grows value while, at the same time, shows the fiscal discipline required to create a highly productive, highly profitable company. And we intend to be leaders in the rare disease space. That's our summary, Gena. Hopefully, that helps give you, your listeners a snapshot of the big picture.

Sure. That's very helpful. So maybe we'll start with your -- the GSDIa program. So for the data update in second half this year, will you provide the longer follow-up date of Cohort 1, 2 patient? Like, will you use a 5-gram cornstarch regimen for the fasting challenge? And will you keep that for the remaining like future potential pivotal study?

Yes. So our plan is [indiscernible] we'll present an update on all 3 cohorts and include where we are on our steroid Cohort 2 and the fourth cohort. So we'll give you that update both on how they're doing overall, starch reduction and other parameters. The time to hypoglycemia test, which had a change in its design to help reduce the amount of insulin surge that was occurring in these patients, will continue to be used going forward. We think that the smaller amount of starch is a little more -- is more appropriate. So we'll put out an update on all of that for GSDI this year, including where we are on regulatory. So we're encouraged by what we're seeing so far, which is everybody is responding and, over time, patients getting better. And those patients out now more than a year are showing durability so far. So we're encouraged with what we're seeing with GSDIa.

Okay. And then you did mention you will start the Cohort 4 with the prophy, which is understandable and seems like with all -- with the prophy treatment seems more consistent. So the -- but you did say the timing of Phase III initiation will not be impacted by Cohort 4. If you can give a little bit more color how -- regarding the Cohort 4 data, how would that impact actually Phase III trials and then how you incorporate that into your Phase III?

Well, our plan for both 301 and 401 was to use prophylactic steroids or earlier-onset steroids, in other words, not waiting for transaminase rises to -- or that what we think going faster is better at reducing inflammation and catching it more early before it gets going. We also think it's a lot more convenient in the commercial setting than managing transaminase measurements every few days in the commercial setting. So we think these are things you want to do in Phase III, is tune the process to match what we would want to do in the commercial setting. We'll have treated those 3 patients, we expect, by the time of the update, and we would know how they're doing from a safety standpoint. We wouldn't have very much efficacy information since that's later in the year, and both that data and the OTC data were delayed in part because of the COVID shutdown of centers during the summer. But we'll put out what data we have on it. What we believe is that we'll go ahead with prophylactic steroids in Phase III, and we're not going to wait for more data from the GSDI Cohort 4. We think that prophylactic steroids are pretty widely used now, and so we don't think it is a fundamental change in approach nor would we expect a fundamental change in how the patients respond. But we're still planning to have the start of the study in the first half. And obviously, we had hoped to originally start it at the end of the year, but with COVID delays and so forth, it put us in more of a position of being in early 2021 for GSDIa Phase III.

Okay. Emil, so for the prophy regimen, is that pretty similar across different trials? Or you will still have to optimize. It depends on the disease and the [ transgene ].

It's pretty standard across of 1. I think most people are using a standard dose of 1 mg per kilo. Although maybe in the Duchenne programs, where they are already on steroids, they might be using a higher dose. It's usually around 1 mg per kilo. And it's a question of a dosing period of maybe a month and then a titration off. So it's something like 6 weeks or so of steroids, maybe 6 to 8 weeks, depending how fast the taper is. I think it's a pretty widely used story. I think the question is, will you have enough steroid coverage so you don't have any reemergence of transaminase levels for the length of time might be one of the questions, the variables, which we'll find out as we move ahead. But our expectation is that a month of full dose and then some weeks of taper would be sufficient to manage any transaminase elevations that might have been expected.

Okay. And then last question regarding the GSDIa program. What has been the FDA feedback on the approvable endpoints?

Well, we're having our discussion with the agency, and we're continuing to provide information on the approach. I believe we'll be able to get to the endpoint we are talking about, which is the maintenance of good control with the reduction in cornstarch. I think the key is that what we're saying is that using CGM monitoring, continuous glucose monitoring, will verify that their control is equal or better to where they were while we're also reducing their cornstarch, showing that we can obtain that good control without the need for large amounts of cornstarch. And so we believe that's a fundamental approach that makes sense. And we'll work with the agency on the details. But this is a new endpoint. And honestly, it's a disease they've never seen before, and it's never been studied before. But based on the fact we're looking at glucose and glucose is a well-described endpoint and the fact that cornstarch essentially is glucose replacement therapy, I think those are stories, I think, that can be put together. I think it is clearly the best endpoint because it reflects the most clinically important thing. The thing that bothers GSDI patients every day is taking cornstarch and being afraid of going low on their glucose, which means every day, they're thinking every few hours of mixing the slurry, drinking it, carrying the water, carrying the starch with them wherever they go and doing this every few hours right after meals for morning, midday, afternoon, bedtime, middle of the night. So we think it's a core clinical result for them. And we know from the patients who have had that reduced 75%, 80% or more that it's life changing because they can go to school all day or work all day and not have to bring cornstarch with them, not wake up at night for it, and maybe they're doing a little morning, a little in evening. But we think that's such a tremendous change for patients that we're comfortable it will be acceptable once we provide enough support for it with the agency.

Okay, very helpful. Switching gears to OTC program. So for your current -- given your current plan, you wanted to include patients with both high ammonia and normal ammonia in the baseline for your Phase III. So do you -- for your Cohort 4 patients, any thoughts on a patient baseline regarding the ammonia level to help you understand better on certain patient population?

Yes. For Cohort 4, we didn't alter the inclusion criteria. So the inclusion criteria still have 100-micromolar limit for ammonia, which means that will be -- should be similar patients to the one we've already treated. In the ones we've already treated, even with that criteria, there were 3 patients in that arm that during the 24-hour monitoring showed an elevated ammonia. Just this goes to show you that during a 24-hour cycle, they have periods where they swing high, swing low. So we're not studying that really in the prophylactic steroid arm. It's not going to give us any more answers, and it's only 3 patients. So the main thing is to look at safety of steroids and to make sure that they are able to do this prophylactically and to assure that the transaminases are protected. And also, we'll get a chance over time to see how that affects the efficacy. But at minimum, we think it could be the same. At best, it would be somewhat better, we would believe, based on everything that's been studied in prednisone treatments so far with AAV gene therapy.

Okay, okay. Very helpful. Regarding the Cohort 4, have you already dosed any patients?

We are dosing in both groups. We have dosed in both, yes. But we're -- we'll provide an update at the end of the year where we are and how much data we have at that time.

Okay, okay. Very helpful. I'll now move to Angelman syndrome. Before asking a specific question, maybe can you remind us the natural history of Angelman syndrome patients based on the CGI score?

Well, the Angelman patients, in general, gained some ground in the first 2, 3 years of life, but they tend to plateau on their development and have a very flat and almost no -- very little variation over time. So the natural history studies looking at school-age kids or similar to the age of kids that are in the study would say they don't really change much during that period at all. They don't gain ground, lose ground. It's pretty static. So I think if there is a gain of ground, it's very small, very -- and it's very slow. So I think that's kind of the base state that most patients are at with Angelman. And it was the way those -- the 5 patients that were in the study were at going forward. They had been relatively stable, not improving, not declining.

Okay. And then based on the current safety profile, we did see a different safety profile from SPINRAZA. Is it fair to say that current dose is much lower than SPINRAZA?