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Ultragenyx Pharmaceutical Inc
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Good day, and thank you for standing by. Welcome to the Second Quarter 2021 Financial Results and Corporate Update Conference Call. At this time, all participants are in a listen-only mode. After the speakers’ presentation, there will be a question-and-answer session. [Operator Instructions]
I would now like to hand the conference over to your first speaker today, Joshua Higa, Director of Investor Relations. Thank you. Please go ahead.
Good afternoon, and welcome to the Ultragenyx financial results and corporate update conference call for the second quarter 2021. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com.
I am Joshua Higa, Director of Investor Relations. Joining me on this call today are Emil Kakkis, Chief Executive Officer and President; Camille Bedrosian, Chief Medical Officer; Erik Harris, Chief Commercial Officer. Mardi Dier, our Chief Financial Officer had an unavoidable flight delay, and is not able to join us on today’s call.
I would like to remind investors that this call will include forward-looking statements within the meaning of the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995, including but not limited to, the types of statements identified as forward-looking in our annual report on Form 10-K that was filed on February 12, 2021, our quarterly report on Form 10-Q that will be filed soon and our subsequent periodic reports filed with the SEC, which will all be available in the Investors section on our website.
These forward-looking statements represent our views only as of the date of this call and involve substantial risks and uncertainties, including many that are beyond our control. Please note the actual results could differ materially from those projected in any forward-looking statement.
For a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward-looking statements, as well as risks related to our business, please see our periodic reports filed with the SEC.
I will now turn the call over to Emil.
Thanks, Josh, and good afternoon, everyone. I want to quickly reflect on our progress mid-year and note that we're approaching a period of significant execution on our clinical programs in the second-half of this year.
For those who are newer to our story, we're a diversified global commercial rare disease company with three products approved for four indications. We now have one of the broadest clinical portfolios among rare disease companies in terms of modalities and indications, and one of the most prolific late-stage pipelines of both gene therapy and rare disease. It is a testament to our ability to identify great science, do effective deal transaction to drive that work forward in the development of our 11 years as a company.
We are now on track to initiate four pivotal clinical trials over the second-half of this year. And these include Phase 3 studies for two of our gene therapy programs DTX401 and DTX301 in GSDIa and OTC, respectively. Two, a seamless Phase 1/2/3 study for gene therapy target UX701 in Wilson Disease. Finally, a Phase 2/3 pivotal study for UX143 in osteogenesis imperfecta.
Additionally, we will begin our first mRNA therapy a Phase 1/2 study for UX053 and GSDIII. Finally, GTX-102 developed by our partner GeneTx will now be back in the clinic treating Angelman patients again.
I'll begin with the Angelman program and then I'll summarize our clinical and commercial progress before handing it over to the team to provide more details. We previously announced in May in June, the Health Canada and the UK’s MHRA approved a modified clinical protocol to begin dosing, pediatric patients with Angelman syndrome in those regions. These approvals followed review by both regulatory bodies of the clinical data on the first five patient in the U.S., as well as abundant non-clinical data.
They agreed with moving forward based on both the promising activity seen at the first lower dose of GTX-102 before any signs of serious adverse event had occurred, and extremely high unmet medical need across the 60,000 patients and their families. We're now working closely with our partners GeneTx to wrap up the remaining logistical details to get sites enrolling and dosing patients.
In the U.S., we continue to make progress in our discussion with the FDA for resuming study. Those discussions have been productive, and we have received green from the agency on a dose administration plan for naive patients. The agency has requested us to bolster the protocol with some specific additional neurological assessments and documentation to verify the safety of the GTX-102 during study conduct, and demands to study closely. We'll make further simple adjustments to protocol based on those feedback in order to get clearance to resume the study in the U.S. This time the FDA has asked us to hold back on retreating the prior treated patients.
As we have noted before, we plan to provide a preliminary data update from some patients through GTX-102 either ex-U.S. or in the U.S. by the end of the year. The amount of data made be limited based on the timing that we expect to treat the first cohorts of patients. Overall, we're enthusiastic about the process for treating Angelman GTX-102 based on everything we know today. We're looking forward to getting this treatment developed.
Shifting to our gene therapy franchise who has completed all of the known requirements to initiate three pivotal studies in GSDIa, with DTX401 OTC deficiency with DTX301 and Wilson Disease with UX701.
At the ASGCT conference in May, we announced the positive longer-term data from the DTX401 Phase 1/2 study showing a 100% response rate across all nine patients treated, and a durable response extending to two and a half years. Similarly, we shared positive long-term data from the DTX301 Phase 1/2 study, the shorter response from all three patients at the Phase 3 dose, and total six of nine responders in the first three cohorts of patients enrolled. These patients maintain or improve their response up to three years following treatment. The teams are in steady startup mode for the pivotal studies and we expect them to get going soon.
Our proprietary and commercial quality HeLa manufacturing platform will be the basis for the next generation of Ultragenyx gene therapy products, starting with our program for Wilson's disease and extending to our preclinical programs for Duchenne Muscular Dystrophy and CDKL5 deficiency, a neurodevelopmental disorder.
These latter two preclinical programs represent our first non-liver targeted gene therapies, and address much larger patient populations. We will provide updates in these programs later this year.
Beyond our gene therapy work, we mean on track to initiate two additional clinical programs this year. One is UX143 or Setrusumab, our recently licensed antibody for osteogenesis imperfecta or OI. Our partner's already generated promising results in adults with the OI showing substantial improvement bone density. Based on our review of the science both clinical and non-clinical, we are convinced that the enhancement of bone production via the anti-sclerostin mechanism will improve bone mineral density in a productive manner that will improve bone strength in patients with OI, by making new bone right where bone stresses as needed, and disappear then to purely antiresorptive actions, for example, bisphosphonates.
This should decrease fracture and so potentially prevent the defamation of spine and bones that comes with repeated fractures early in life, especially in the patient with Type III or Type IV OI.
The clinical study will initiate will focus on pediatric and young adult patients that have frequent fractures. We are planning the initiation of a Phase 2/3 study with this population by the end of the year.
The other program is UX053 and mRNA program for glycogen storage disease Type III. This first mRNA program for our license with Arcturus Therapeutics is also expected to begin enrolling a Phase 1/2 study by year-end.
Now turning to our commercial programs, we had another solid quarter with significant revenue increases from Q1 in 2020, with progress over the globe. The Crysvita particularly continues on a strong growth trajectory even as we entered the fourth year from its initial approval in 2018. It’s continued uptake is driven by both North America and Latin America.
In North America, penetration in the adult XLH population is a major driver, in line with our expanded patient ID and broader physician outreach efforts. In Latin America, our team's efforts in supporting patient reimbursement have helped drive increased volume, revenue, and patients are staying on Crysvita once started on compliant with their regimens.
That was a testament to how much it helps patients with XLH. We also have a number of multi-generational families on Crysvita, now there's nothing better than to get notes from families comment and how much their lives across generations have changed. Crysvita is a paradigm shift in XLH treatment. We're happy to be at the forefront of making this happen.
Our strong launch with Crysvita has been followed by our successful launch Dojolvi, which has now been on the market for about a year. Our team established great momentum, identifying patients, securing reimbursement coverage, facilitating new start forms. The strong start shows how much a new option was needed for LC-FAOD, and tells us that Dojolvi will also represent a paradigm shift in the management of LC-FAOD.
I'll now turn the call over to, Eric, to elaborate on our commercial progress in the quarter.
Thank you, Emil, and good afternoon, everyone. Before I get into the details of the commercial performance for the quarter, I'd like to thank all of the teams for their work and dedication during what are still uncertain times. While most states have reopened, the teams have shown an ability to adapt and overcome challenges within this new environment of conducting business.
Crysvita had another strong quarter growing 6% versus the first quarter of 2021, and 38% over the second quarter of 2020. Within the North American region, second quarter revenue grew 15% versus the prior quarter, as the seasonal reimbursement effects normalized.
Crysvita revenue in Latin America declined quarter-over-quarter, but this is driven by an uneven ordering patterns, and is not reflective of the underlying demand. Given the strong demand and execution we have seen in the first-half of the year, we continue to affirm the 2021 guidance range, we previously provided for revenue in Ultragenyx territories of $180 million to $190 million.
In the United States, we are continuing to make inroads beyond major endocrinology and metabolic bone centers, and into the community clinics where we are finding more and more adult patients. Early on in the launch, adults made up 40% of the patients treated with Crysvita. Today, as the total number of patients on therapy has grown significantly, so too has the portion of adults who have received Crysvita. We are now at approximately a 50/50 split between adults and ped on Crysvita therapy, mainly driven by the work the team has done in the small, harder to reach community clinics.
As the teams leverage and expand upon investments that were made over the last year, we are confident we will continue to find more patients with XLH and TIO who could benefit from Crysvita.
Shifting quickly to Latin America, we continue to see growing demand for Crysvita across this region. As is typical, full reimbursement approvals in Latin American countries can take some time. But the base of patients continues to expand as more on branded injunctions and gain access to main patient cells.
In Colombia, we recently received regulatory approval for treatment of XLH in adult and pediatric patients one year of age and older. Patients had been on therapy through named patient programs, but this will significantly streamline the process for patients to receive reimbursed therapy.
In Brazil, we are in the final stages of negotiating full reimbursement, and in the meantime continue to receive orders from the Ministry of Health to support the patients who have been granted an injunction to receive this therapy.
Turning now to Dojolvi, which was approved for the treatment of long chain fatty acids oxidation disorders or LC-FAOD by the FDA in June 2020, and by Health Canada in February 2021. Recall there are an estimated 2,000 to 3,500 patients in the U.S. with LC-FAOD. As of the end of the second quarter, we have received approximately 270 completed start forms. This represents significant penetration into the prevalent patient population at this point of the launch. These start forms have come from more than 130 unique prescribers of Dojolvi, with approximately half having written more than one prescription. This has led to approximately 220 patients on reimburse commercial therapy, and continues to speak to the broad interests we are seeing from the physician community and strong support from payers.
As of the end of June 2021, payers are providing broad coverage for patients with LC-FAODs. The time from completed start forms to reimburse therapy continues to outpace what we saw, at a similar point in the Crysvita launch. It is great to see so many patients in the U.S. with LC-FAODs quickly and successfully navigating their insurance policies.
Outside of the U.S. there are a number of patients who have received Dojolvi through named patient and early access programs. We are continuing to work with regional regulators to gain full approval to treat all patients who could benefit from Dojolvi. In Brazil, we have had positive discussions with the Ministry of Health, and are hopeful about the review process with this agency.
Looking forward to the second-half of the year, the commercial and field teams will continue leveraging many of the tactics that were developed last year. We have learned how to adapt to this new environment and will continue to find more and more patients, who could benefit from Crysvita, Dojolvi and Mepsevii.
With that, I'll turn the call back to, Joshua, to share the financial results.
Thanks, Erik. We issued a press release earlier today that included a financial update, which I will briefly summarize. Company revenue for the quarter ending June 30, 2021 totaled $87.0 million. Crysvita revenue in Ultragenyx territories was $44.7 million, including $41.8 million from the North American profit share territory, and net product sales of $2.9 million in other regions. Total royalty revenue related to the sales of Crysvita in the European territory was $4.9 million.
As a reminder, ordering patterns in Latin America will vary from quarter-to-quarter. In the first quarter 2021, we received a large stocking order from Brazil's Ministry of Health to support the patient demand in that region. We are confident revenue from this region will continue to grow over time, driven by strong underlying demand. But ordering patterns will be uneven in the near-term as we work through the reimbursement process.
Dojolvi revenue for the quarter was $10.0 million. As we have noted before, we will not be providing revenue guidance for Dojolvi in these first quarters of launch. We believe the metrics Erik discussed better describes the success we are seeing so far.
Mepsevii revenue for the second quarter 2021 was $5.4 million. We expect these revenues may modestly increase over time. Second quarter 2021 revenue also includes $22.0 million related to tech transfer as part of our strategic manufacturing partnership with Daiichi Sankyo, around our HeLa PCL and HEK293 Technologies. Through the rest of this year, the revenue recognized will taper significantly, as the tech transfer activities come to a close. Additional details on this revenue recognition can be found in our annual and quarterly reports filed with the SEC.
Our total operating expenses for the quarter were $169.8 million, which includes research and development expenses of $113.2 million, SG&A expenses of $53.4 million, and cost of sales of $3.1 million.
As a reminder, we expect our R&D costs this year to increase versus 2020, as we support three pivotal gene therapy studies, the UX143, Phase 1/2 clinical study in OI, the Phase 1/2 study for our most advanced mRNA program, UX053 and GSDIII, and a number of other pre-clinical activities as we get ready to advance the next programs into the clinic. We also expect SG&A to modestly increase in 2021, as we continue to support the expansion and launches of Crysvita, Dojolvi, and Mepsevii.
For the quarter ended June 30, 2021, net loss was $122.4 million, or $1.81 per share. This compares to net income in the same period of 2020 of $25.3 million, or $0.42 per share basic and $0.41 per share diluted. The net loss for the second quarter 2021 includes a $31 million decrease in the fair value of investments in equity securities, as compared to a $95 million gain in Q2 ‘20.
Net cash used in operations for the six months ended June 30, 2021 was $224.7 million, compared $7.8 million for the same period in 2020. Net cash used in the first-half of ‘21 includes the $15 million upfront payment for the closing of the Mereo license and collaboration agreement, compared to net in the first-half of 2020, that included $134.9 million of operating cash received from Daiichi Sankyo related to collaboration and license agreements.
We ended the second quarter with approximately $974 million in cash, cash equivalents and marketable securities. This puts us in a strong capital position to reach key clinical and commercial milestones as we continue executing our development and commercial strategies.
I'll now turn the call over to Camille.
Thank you, Josh. And I too wish everyone a good afternoon. Today, I will focus my remarks on providing an update on GTX-102, being developed with our partner GeneTx for the treatment of Angelman syndrome.
Angelman syndrome is a devastating neuro genetic disorder, with a broad spectrum of disease manifestations that affect multiple important domains. Last year, we reported surprisingly early positive efficacy data from the first five patients treated in the Phase 1/2 study of GTX-102 that indicated substantial improvements in multiple domains in all patients.
We also reported all five patients had a great one or two serious adverse event of lower extremity weakness that has fully resolved. At the first presentation of the SAE, we paused dosing and enrollment in the clinical study. Since then, we have run extensive tests to confirm that this SAE has been fully resolved in all five patients.
Furthermore, we shared extensive clinical and non-clinical data with regulators, and have had productive discussions with regulatory agencies, including Health Canada, the Medicines and Healthcare Products Regulatory Agency, or MHRA in the UK, and the FDA.
Outside of the U.S., both regulatory agencies have reviewed our data and have given us the green light to begin treating patients with GTX-102. The agencies agreed with our plan to begin dosing in two parallel cohorts with a modified dose titration and administration plan. One cohort will start at 3.3 milligrams for patients under eight years old, and the other at 5.0 milligrams for patients aged eight to 17-years. Trendelenburg or a head down tilted positioning of the body, and an artificial CSF flush should help reduce the local contact time, and help the ASO reach the cisterna magna as it is diluted, and through circulation distributed to the brain.
Careful titration to higher doses may be evaluated on an individual basis, after two repeat doses had been first administered to allow the exploration of a dose that is both substantially affected in at least two domains, without causing a safety event. Dose escalation is capped at 14 milligrams for a single dose. This new dosing plan is within the observed range of clinical and non-clinical activity, but below doses associated with SAE.
In the U.S., we have had a number of productive discussions with the FDA, where we discussed the nature and complete resolution of the SAE, as well as our plan to resume dosing patients in the United States. Following a Type A meeting, we submitted a protocol amendment.
Based on feedback we received on this amendment, we believe we have agreement with the agency on a dose and dose administration strategy to treat naive patients. The agency asked that a few specific additional neurological assessments be added to the protocol before we resume dosing in the U.S. We will make these changes and look forward to resuming the treatment of patients with Angelman syndrome in the U.S.
We and the GeneTx team have received numerous inquiries from families looking to enroll their children in this study. The data generated will confirm we can safely dose patients with GTX-102 and will inform the loading and maintenance dose regimens, as we move to the next phase of development.
With this update, I will now turn back the call to Emil. Thank you.
Thank you, Camille. Before we close out, I'll provide a quick reminder of the key upcoming milestones for Ultragenyx. For GTX-102 and Angelman syndrome, we will dose patient in Canada later this quarter and provide some summary data by the end of the year. We also expect to resume the study in U.S. adapted to the FDA’s request.
For our three pivotal gene therapy studies, DTX401, DTX301 and UX701, all the products have been manufactured and released for use in studies in sites around the globe and identified and patient finding efforts are underway as the final operational tests are completed before we begin dosing patients.
For UX143 osteogenesis imperfect, we reached green with the FDA on a final pivotal study in pediatric and adult patient, initiate that study by year-end. For UX053 and GSDIII, we tend to move our first mRNA therapy in the clinic with a Phase 1/2 study. As you can see, we're executing on all fronts, with early and late-stage clinical trials in various disease areas and therapeutic modes as well as in commercial. This will set us up for multiple important clinical readouts over the coming 12-months, as well as pivotal study data from at least four programs over the next couple years.
With that, let's move on to your questions. Operator, please provide the Q&A instructions.
Definitely. Your first question is from Maury Raycroft with Jefferies. Your line is open.
Hi, thanks for taking my questions. So I was wondering if you can elaborate on what the additional neuro assessments are that FDA is asking you to use for Angelman. And can you book and how many patients and how much follow up you could have to report later this year?
Sure. Well, we've agreed on what the assessments are the sort of they want, how we're documenting with the training of the person is, who it is. They just want like a little more of logistical detail. But these are just really careful neuro exams. And we're doing some deliberate electrophysiology, and we'll also have will the imaging when necessary. They also want us just to be certain of what triggers what kind of action on our part, what you do when you find things. So it's a little what I'd call logistical management detail. But I think fundamentally, we have the big pieces put together, it's why we're confident we'll get that figured out. It's unfortunate it's taking time to do this. But I think we're finally there.
Now on the how many patients, it depends a little bit of how many patients get treated in the UK, and in Canada. The sites already have patients inquiring, they've gone through some of the ethics committee. So it's a little bit more of the last logistical steps. We said before, we’d expect to have a few patients treated through a few doses, that we would, by the end of the year. The exact number, I think it's hard for us to say, but we'll have some data on a few patients. And we should probably have most of the patients in the first two cohorts, at least receive one dose by the end of the year.
So we'll put out whatever we do have, but it will be limited. It won't be an extensive amount of data. But we do believe it'll give us least a sense of are we moving in the right direction with the program. Our confidence is that if we give patients for three or four low doses that load them, and they will begin seeing these the clinical effects we saw before, so without having the adverse events, so we'll get start to get a read on that before the end of the year.
Great. Okay. Thanks for taking my questions.
The next question is from Tazeen Ahmad with Bank of America. Your line is open.
Hi, good afternoon. Thanks so much for taking my questions. Emil, another one on Angelman, if I may. So you made in your prepared remarks, the comment that the agency has asked you not to start redosing the previous patients. Is that pending approval for what you're going to do for protocol for the new patients that you would add? Or, is that something that would have to be separately discussed? And then I have a follow up?
Yeah, I think their view right now is that we don't have perfect knowledge of what the reaction will from, and so they'd want us to get patients treated that haven't seen higher doses and just see if it's safe to do and that works. And then we could rediscuss what to do with retreating patients. But we don't have perfect knowledge, what the mechanism is. What we have said and we believe the data we have suggests it's a local chemical irritation type effect, because there's no cellular response. There's no antibody response, it's really kind of a local contact thing.
But we don't have perfect knowledge and mechanism. So it's mainly about going into naive patients' lower dose. That way we know it's nothing about the history of exposure, we're now dealing with the low dose alone and can look at it in a clean way. After that, we'll certainly have to get back to retraining the same patients we saw before. But we don't think this changes our overall timeline of what we do.
I think we can get the data that we need. It just really is tough for those patients who were so excited and want to get retreated. For them to have to wait more time is disappointing for them, but it won't affect the overall program. But we do feel for them. We're going to work and getting them treated as soon as we can.
Okay. And then as a follow up, is it safe to say that the FDA is asking for additional information relative to what the UK and Canada asked for? And if that's the case, what's prompting that?
Well, the actual method we're using in Canada and in UK regarding evaluations and safety monitoring is actually the same. It's the same. It's a question of how much details we provide them, do we have a checklist form, is there some other let's say, operational structure and verification of training, et cetera. They sort of want more detailed rigor around the same things that we're doing there and doing here. So it's not like they're making us do extra things, really. It's really the same safety assessments.
So I think they're just being very conservative. And they want great assurance that we're going to be careful about what we do, but of course, we will. But I think you can be careful by having really great neurologists who are insights to take care of patients carefully. And then the question is how much documentation makes that better or not. And, I think you can do it. If you have great people, they'll do a good job. So that's the difference.
Okay. Thank you.
Your next question is from Gena Wang with Barclays. Your line is open.
Thank you. I have one question regarding Angelman clinical endpoints. Some doctor feedback suggests CGI has some limitations, and rely too much on parents' feedback. What other measurements you would include for the Phase 1/2 such as Baileys or Violin [ph], that's what doctors recommended? And then, quickly another question regarding DMD. Just wondering, are you on track for the R&D filing second-half this year?
Did you say DMD?
Yeah. DMD.
Alright. Well, we'll follow up with that. Alright, so on the CGI or the patient feedback story, whatever they're telling you, they're not quite giving the complete story because our evaluations in the trial what GeneTx has been doing involve -- well, there's a caregiver part. But there's also psychologists administer tests, like the Bailey's were administered by people. And then we have other ones that the investigator measures and does themselves, by physically watching the patient do things not dependent on the patient. So we have really three different parties reporting the data in the data that we've already shown you. All right. That's all complimentary and supportive.
In addition, that we have objective measures like the Delta power, EEG measures, right, or the Active Mayo [ph], which showed other things. So there's a number of different things that I would say are independent. CGI from the physician, by the way, depends also what he sees the patient too. But I appreciate their point, I think we would want to make sure and this is why we read out data on these multiple methods to make sure we have confirmation by independent observers, and not be swayed by just a family's view.
I know also for a fact that our PI at Chicago saw videos of the patients doing things that the parents had said they had done, so they actually were shooting videos of their kids, because they're so excited about them speaking words, and other things. So she also saw video evidence of what they were doing, rather than just patient report, just to be clear, like objective video evidence of things. So, we're confident that the things we're seeing are real, and are meaningful.
Now let's talk about Duchenne Muscular Dystrophy, what we said is we're going to update the street about where we're at on the program. We're not filing on IND by this year. We've never said that. But we said this year is we're focused on creating a large scale commercial manufacturing system using our HeLa system, and that we would put out information about that production system. It's going very well, our expectation is to be able to put out data on a large scale methodology using our HeLa 3.0 technology later in the year on Duchenne and update you on our non-clinical program. At that point in time, we would lay out potentially the timeline to an IND but it's not the end of this year.
Okay. Thank you.
The next question is from Yaron Werber with Cowen. Your line is open.
This is Brendan on for Yaron. Congrats on the progress. Thanks for taking the questions. Just a quick one from us. I guess to keep on the same line, an Angelman. I was kind of just hoping to see if you can maybe give us a little bit more color on the timing for the UK study. I know you said things like Canada is pretty close to the first doses. Just wanted to see what's left maybe getting drug in some patients and the UK and if we might get any of those in the urine data.
And then just wanting to see also if you mentioned that you set it on dosing scheme administration with FDA, wanted to kind of see if you can tell us if it's the same structure you're using in the UK, in Canada, or if you're thinking about a different design for that. Thanks.
Okay. So the UK is on track, I mean, it could be UK or Canada in terms of treat comparisons within weeks of each other, so it won't be that much different. We would expect to have some UK patients treated, there's a great deal of enthusiasm from the UK patient community getting enrolled. So, once the site's open, we expect them to be able to enroll.
And remember that study will have two patients below 2.8 first treated, and then a couple of dose, and then the additional patients will get treated. All right, till they're six and six treated. So that's, we'd expect some UK patients.
Now you're asking about the U.S. protocol, U.S. protocol will also have monthly dosing, will have different dose. But the methodology will be simpler in the U.S., in fact, not identical to what the UK and Canada is doing because the FDA has made specific requests. We have understanding with them about the dose administration strategy that we're going to use in the U.S. But it is a little bit different. It is monthly dosing similarly, but the method so far will be a little bit different based on FDA’s input.
Okay, great. Thank you.
Your next question is from Joon Lee with Truist Securities. Your line is open.
Hi, thanks for taking our questions and for the updates. I have a question on UX053 GSDIII. We're interested to hear your views on the use of modified versus non modified mRNA given the precedent set by Moderna, BioNTech and CureVac. Curious if the signals some potential headwinds UX053 given Arcturus uses the unmodified mRNA. And some KOLs seem to think that urethane might have contributed to weak data for CureVac and they also point out to double stranded RNA as a potential trigger innate immunity. And so curious what your views on that are on that? And sort of what kind of biomarkers are you hoping to collect from this initial data to assuage any concerns there? Thank you.
Yeah. So, we think the issue of the innate immunity stimulation of mRNA is very important. And we actually do several things to design. We design the mRNAs very carefully to assure that they don't induce innate immunity response. And we actually use peripheral blood monocytes white cells for patients to actually test our mRNA to determine they're not having significant amounts of double stranded in how we purify prepare them.
We have used modified on nucleotides. We're using mRNA. So we just have to make sure that they're translated efficiently. But we haven't disclosed all the details of that. But we know our mRNA is not stimulating human white cells, which we think is gives us a handle on that particular issue. And we know the expression is as substantial in terms of how much enzyme can be made from the mRNA product. So the whole issue with regard to the COVID vaccines, I think, are more complex than just the RNAs, frankly. So I think there's a lot of other aspects like the LMP themselves, which can't -- lipids being used, et cetera. Those are factors that matter.
The [indiscernible] that we're using is a novel one that occurs developed, that is metabolizable and 99% cleared within a couple weeks from the body, unlike some of the other lipids. So it's a very appropriate one. It releases early and this gives us better expression. So we think the LMP is a factor two in how this works. But the mRNA quality, we do a lot of work in optimizing how we prepare purify and use of modified nucleotides as needed.
Thank you.
Your next question is from Salveen Richter with Goldman Sachs. Your line is open.
Hi, good afternoon, and thank you for taking our question. This is Elizabeth on for Salveen. A question on the Angelman program, so I know previously, you've sort of discussed expanding the program to include other genetic types outside of the most severe solution based patients. Just wondering how this would work in terms of the trials and progress or if it's more of a future consideration?
We definitely think the other genetic types deserve to be treated and we think the ASO if it works in the deletion type, it will work in the other types based on the mechanistic understanding. Our plan right now is to focus on the 77 patients of deletions for the program we're conducting. However, we would probably put in place a second study to look at other genetic types.
The reason to focus the main pivotal study on the deletion type is because they are more severe. Therefore, any improvement you see in language communication, which is one of the main things that patients are most interested in would be clear if we have a mixture of patients who have varying degrees of communication skills, and words, et cetera. It would just create difficulty in a pivotal randomized study.
So we'll focus on those but we are not going to forget the other types and put some program in place to deal with the other types, as well. But creating heterogeneity in the main body of them big study is, is one of the ways you can create trouble for something that's doing great. So we wouldn't do that.
Thank you.
Your next question is from Joseph Schwartz with SVB Leerink. Your line is open.
Thanks very much. We noticed a couple questions on Crysvita. First, we noticed that the label was updated in Europe to allow patients to self-administer therapy. And we were wondering, what impact do you expect this to have if any? And do you think we could see a similar change take place in the U.S. at any point in the foreseeable future?
Thank you, Joe. But in the U.S. right now, we actually have temporary authorization from the FDA to allow self-ministration which is going on already, because of the pandemic. We haven't submitted the change that at this point we have done the human factor study. The drug administration is very similar to what you might do for any other subcutaneous drugs is something very special about the injections or problems. So it certainly could be added. It has complexity, though in the U.S. because we have to deal with the different systems, whether it becomes a medical product, a hospital product, or home product or not a part B product.
So there's some complexities in the U.S. at this point in time, but our patients are doing self-administration. And I think in the long run, we would certainly move in that direction. We haven't had a big compliance issue. And I think one of the things is important just to know that we supported right up front and do include in the class of drug, getting a home nurse that comes to your home inject you. So the 85 plus percent of patients are getting their stuff at home already. So the benefit of self-ministration is you don't have someone show up at your house.
On the plus side, there's a lot more confidence that you're going to get your injection on time since it's an appointment. But we want to make sure it's as convenient as possible, because this is a lifelong treatment. So we'll look at self-administration in the long run, but so far, the home nurses are working well and some of the patients are getting it, are doing it for now on the temporary authorization.
Okay. That's helpful color. Thanks. And then has the need for Brazilian patients to use the label system to gain access to Crysvita but holding back adoption there to an appreciable degree? Can you quantify the impact you'd expect to see on Crysvita Brazil sales from potential end visa approval?
Well, we have the approval, and we are getting injunctions and Ministry of Health orders as the lumpy ordering pattern we're seeing, but it is there we are getting orders that it's growing over time. What we're talking about today is getting formal approval of the organization within Brazil that actually determines government reimbursement.
With that it would help get more regular reimbursement for Brazil. So that that is near the final stages. And once that's completed, we'd expect that would help boost Brazil further. So we wouldn't have as much of the logistical challenges of what you're doing with the injunction approach. Is that answer to your question?
Yeah, it's helpful. I was just wondering, is there any way to quantify how much the current system has been holding back sales? Or, how much could you get a boost from?
I don't know. Erik, do you think there's so many color on that I don’t have any sense for what that would be? I know we have a lot of patient want to get on drugs. So it's definitely holding back something. Erik, do you have any sense for how many patients are in demand, I mean, rough sense? And how many actually navigated the net the process?
Yeah, we've done a good job of identifying patients and many of those patients have sought injunctions. And as stated, many have received injunctions and are receiving reimburse therapy. I would say to the magnitude of about two to threefold patients that have been identified and are seeking reimbursement versus that have received injunctions. So, there's some upside once we receive formal reimbursement.
And one thing I do want to point out, just to piggyback on what Emil stated that in the first quarter, we did receive a positive opinion supporting reimbursement in Brazil. We're just working through that final stage, which is establishing clinical guidelines, which is the next step in the approval process, and we expect to complete that sometime in the New Year.
Very helpful. Thanks again.
Your next question is from Cory Kasimov with JP Morgan. Your line is open.
Hey, good afternoon, guys. Thanks for taking the question. On Angelman, has the FDA conveyed this concern before about retreatment? Because it seemed like that was the plan for the go forward strategy in the U.S. until very recently. I guess just wondering for something new that triggered this change in direction?
Well, we had our Type A meeting with them. And, it was pretty clear that they were just concerned of the patient that had a reaction might be more sensitized, established again, and therefore, they'd have trouble determining the safety would have been different, had they have a patient who never had the reaction as opposed to one that did that make sense. So in terms of understanding what's going on, they felt its safer to start with an A patient, and they want us to hold back on that.
There's no new data that helped change their mind. We have no new data regarding things that might cause them to have a more severe reaction, we think, based on everything we have, that they don't have something that we think would prefer that way, but we can't prove the mechanism exactly right. And so without that proof, the agency wants to play it safe with regard to who they expose in the beginning. So, that's the story. There isn't anything new that came out, for example, that would have made that new change. It's just something they finally disclosed to us at the Type A meeting.
Okay. Makes sense. And then I just wanted to try to clear up the dosing you're expecting to use in the U.S., you said it's going to be different than Canada and the UK. Is it that you're going to start with lower doses and work your way up? Or, would it be higher doses here, given you treated some patients?
No, we're going to start a little bit lower. We think that it's still in a range that will load the patients sufficiently over four doses to get a treatment effect. But I think the FDA wants to be more cautious. And so, we went along with what you have to do to get going.
No, absolutely. Okay. Thanks a lot. Appreciate it.
Your next question is from Yigal Nochomovitz with Citi. Your line is open.
Hi, this is Carly on for Yigal. Thanks for taking our questions. We had a couple on a Wilson disease. As far as the target patient profile for the Phase 1/2/3 trial, will you be focused on recruiting patients with established disease? Or is the focus on treating newly diagnosed patients? Just curious if you think there could be an advantage in terms of the magnitude of benefit with UX701 if you're able to capture patients earlier versus later in their course of the disease?
And then secondly, what is your expectation at this point for when we could potentially see some initial data for this program from the dose escalation part of the study? Thank you.
Yes, thank you. So the patients will be the patients who've been or established patients who've already had a key letter. The problem doing naive is it would be very few patients, and it would greatly flow in all mood take a long time. I don't disagree with the thesis that treating patients early before they've changed would allow a cleaner result. But we do believe that since the key letters removed copper by bringing it into the urine, and what we're doing will bring copper into the bile then we will be able to look at urinary copper and show that the copper is no longer ending up in the urine, oozing out of the liver or being culated. It's going to be routed into the bile right. Does that make sense?
So, even though they're on drug, we can determine if the copper pathway is changing in the body. And if the rule of plasma has gone up, so it won't really matter if they are not established and not we can see difference happening. And the truth is there's so many more patients on established therapy, it would take us a long time to do it the other way.
In the long run, though, using naïve patients, I think would give you a cleaner result. I think taking patients earlier in their course, might change people's view what's happening, everyone believes it's just the excess copper. But it's also possible that it's copper not being properly distributed as well. That's part of the symptomatic problems that you're seeing in Wilson, and we think the gene therapy can fix both. So, that's our focus based on the ability to conduct the study and the way we can measure them.
Now with regard to when data, we expect to be able to get the patients enrolled in the dosing relatively quickly. I can't say specifically when that data will come out, but we will put out data could be by the end of 2022. But I'm not 100% certain. It depends a little bit on Delta virus sites execution, but we're up and running, products ready, sites are getting set up.
And we have I think, a very convenient protocol that will be easy on patients, so I think it will help make recruiting easier.
Okay, great. That's very helpful. Thank you so much.
Your next question is from Laura Chico with Wedbush. Your line is open.
Thanks very much for taking the question. Just on Angelman, you've commented in the past on the potential potency differences between GTX-102 and the Roche program, then there's also another program starting from Biogen. I'm wondering if we could just take a step back, and how do you think about the key elements of differentiation in a clinical setting for all these ASL targeted strategies? Are there logical points in which two agents might differ? If this is still kind of evolving, I guess what kind of aspects should we be focusing on as the clinical trials get underway here?
And then just one quick follow up. With respect to the dosing in Angelman patients in the UK and Canada, I think in the past, you've spoken about getting them through the titration getting up to a steady state level. It isn't clear to me how many patients are actually going to be at that range, and especially if we're going to be needing more like three or four doses. I guess I'm just trying to understand how you think the response data might differ this time around versus the prior experience? Thanks.
Okay. So on the competition, we know the mechanism for this algo is special, the patented region is different. It's at the five prime end. I think Dr. Dindo [ph] has shown that is far more potent than antisense algo from other parts of the message, in terms of knocking down the production of the antisense message and in level of induction. I think each ASL could have varying levels of potency and penetration. But I think you want to have high potency across the brain. And you want to bring the mRNA down, I mean, the antisense RNA down far enough to get significant induction of the message.
And we've shown that we can do that with a relatively small amount of drug, and that effect goes across the whole brain to all regions. So, I think the difficulty will be how well the all algos are distributing and how well are they able to knock down? And because all ASLs have toxicities, it's very common, you've seen them a lot of programs, there are drugs that have a lot of potential challenges. The potency will then becoming an added question of therapeutic window.
I do believe if we're able to successfully dose in the single digit range, low double digit and achieve the efficacy we saw that will greatly reduce the possibility of having systemic ASO side effects that you sometimes see, or other neurological effects. So certainly, that's our expectation.
So on the tight dosing and titration story, in the first set of patients, right, we're treating two in each group, and then we're going to add four and four. So it'll be 12 patients total. We'll have 12 patients and from the 12, we'll get a read on where do they seem to be getting the efficacy and what dose are they at.
Once we get that information, we're going to try to look at it and try to make sense of how it's the optimal way to dose going forward. But we've said before, once if we see safety and we're getting good efficacy, we'll take that information and translate it into a dose that we'll use on an expanded cohort of say 30 or 40 patients. Those patients would get a starting dose based on the dose achieved during the titration and use that as their starting dose. Does that help you?
And the idea is that those 30 to 40 would now have a little more standardized dosing regimen, right? That makes sense? So titrate individuals learn a little bit and then standardize it in the next group.
Got it. Okay. Thank you, Emil.
Your next question is from Dae Gon Ha with Stifel. Your line is open.
Great. Good afternoon, and thanks for squeezing me in and congrats on all the progress. Maybe one question on Angelman and then quick one on 401, Emil. So on Angelman a lot of my questions have been answered but just curious on clin trials you have one side in Canada, one side in the UK, which is going back to the variability issue. Will you have a centralized reading for the CGI to make sure that there is a confident vote in terms of the CGI benefit, as well as some of the other benefits that are included?
And then on 401, just curious, given that one of your endpoints measures the glucose control using CGMs, I was wondering if the protocol entails any backups in case CGM starts malfunctioning when you validations for any significant variability that might occur during the study? Thank you.
Sure. So there's really no way to do a CGI centrally because it's an opinion of the physician there, and not everything they're doing in terms of valuing the patient could be centralized, turned into a video. The sites will be trained on the various endpoints. For CGI, there's a global one and then there's individual ones for individual domains, which have specific questions that they answer, and we'll try to do it. We'll do our best for our team to train the CGIs team to train the sides to be able to do these tests.
We also have a number of tests that are not CGI, right, that have basic scoring mechanisms, and are being administered by professionally trained psychologists, for example, as well as some other objective measures. So we won't be relying on CGI to make all the calls. I think CGI will give you a gestalt feeling of what the PI things.
But as we noted, when we presented this data before, you want to look at the other endpoints to show there's an underpinning, right. If having CGI without any underpinning in the rest of the data would be suspicious, right. If someone's just wishful thinking hoping they're better. But if they're really better, there should be something else happening. So we feel confident, we can manage the question of objectivity by using the supporting data.
Now, with regard to 401 CGM controls, while we will have them continuously monitored, we're actually going to take windows of sample time and do the calculations for how they're doing. So if, for example, they had a probe, and the probe fell off and stopped working, we would see the defect, we could take the period of time when they sampled effectively and calibrate it. So they're going to put them on calibrate measure for a period and we'll use the sample periods. That makes sense.
Because if you expected to be able to use all the data continuously for months and months, yes, stuff is going to happen during that period. But we'll have periods of assessment that are in intervals of time, we're going to watch it more carefully more closely. And we'll take windows a sampling that will be where it is verified as operating correctly, calibrated correctly and receiving. So that should help protect us against the kind of digital disaster you're talking about. And we've been thinking about that, too.
I'd also point out the devices collect locally, and then they collect in the cloud too. So it's actually double collected. If anything, we could actually shift the device and do it. But that doesn't stop a patient from having a probe malfunction or something. So you have to include all levels of the problem not just digitally, but on the physical parts connect to the patient, which are probably the bigger source of questions. But we've had good experience so far. We're getting a lot of good data from the patients, so we feel pretty comfortable. We can get this to work without having a lot of trouble.
Very good. Next question.
Okay. Your next question is from Liisa Bayko with Evercore ISI. Your line is open.
Hi. Thanks for taking my question. Just to clarify, so in the U.S., we're just back to the Angelman program. Even though you're starting lower, can you still escalate up to the 14 milligram level?
We'll start lower and see how we do, and then we'll treat the several doses at a lower dose, which, as I said, should still give us enough drug to show an effect. And then, if we establish safety there, we have safety elsewhere, we’ll then apply the FDA to kind of titrate them up. But, we're kind of taking baby steps forward on the U.S., get them tested, get some data, and get comfort.
But whatever happens in the U.S. will not control the future, we will have UK and U.S. sides more than one site doing with all that data together, we'll come up with a plan. I think the agency is being very conservative, it's fairly typical for them. And we are just working our way to get going. But I don't think it's going to affect anything. It will delay our ability to titrate those patients, but we will still have enough drug on board to know that it's safe and to know that it is doing something for them.
Okay, I see. Okay. Thank you, that's helpful. And so there's no -- the max dose is basically not determined, or is there -- because you’d kind of set it up for 14 for the other.
For ex-U.S., we agreed at 14 based on the other authorities with 14 is the max. But in the U.S., we haven't set a max because we're not titrating and we're starting in a low dose, we're going to repeat that multiple times. And the FDA is agreed to that. So we'll get started and start getting some data.
Okay. And then, last thing is just on your gene therapy programs the GSDIa and OTC. I know your endpoints are 48 and 64 weeks. Do you need a greater safety database in that? I'm just thinking back to BioMarin or to file and kind of longer-term efficacy? Or can you really file on that when you reach a primary endpoint that is sufficient to file? Thanks.
Yes, it's good question. I think the key thing here is that we will have 12 patients from the earlier cohorts in both programs that have been exposed, that will give us some sense of durability. Now, so far, it looks durable. I think the challenge with BioMarin is they had some decline activity and the FDA was trying to understand the direction.
Our disease are much smaller rather than hemophilia. Hemophilia has 100,000 patients in it. Our diseases have eight to 10,000 patients one-tenth. So the size of our trial compared to the population size is actually substantially more. So we're taking a bigger sample.
In addition to the safety patient trial, the 12 patient Phase 1/2, it's very likely we might add some additional patients that we have treated, for example of different ages or other situations that we would add to the package. But right now we believe these numbers are fine. And frankly, we have not had any regulatory authority debate on the size of the studies with us.
And remember, the 50 randomized the other 25 will get treated too. So it's all crossovers, you will have 50 patients treated. 52 patients treated, it's pretty a normal safety set or rare disease products. That's not an unusual one. For gene therapy. I think it's good.
Okay. Thanks, Emil.
Thanks, Lisa.
Your next question is from Jeff Hung with Morgan Stanley.
Thanks for taking the question. Most of mine were already asked. So you recently indicated that patient identification because data had come back to pre-pandemic levels. Any additional update on that level since then, particularly given the Delta variant and recent increase in COVID? Thanks.
Yeah, it seems to be going still pretty well. I think it's just people have adapted to the new world. And so we're still doing a lot of virtual work and people are responding and getting things done. So I don't know that we've seen anything from Delta. And I'm not sure if Erik or Camille have something to say about patient ID and delta at this point.
Only thing I would add is that the patient identification has been pretty consistent the last couple of quarters. And the other good thing to add about that is that we're finding more adult patients than pediatric patients, and thus far, have not seen any impact from the Delta variant but it's very early.
Right. This is Camille, I would agree with that. And to Emil’s point, the teams have been working virtually quite a bit, as well as understanding more about the multigenerational aspects of the disease and finding patients in that way as well.
Thank you, guys.
Thank you, Jeff. All right, next question.
The next question is from Joel Beatty with Baird. Your line is open.
Hi, thanks for taking the question. For Angelman, what gives you confidence that the changes you're making in dose administration will help reduce or avoid the lower extremity weakness? And, part of the reason I ask is that since it wasn't seen in preclinical studies, that may make it more difficult to test for.
Certainly, but I think there's two things I would say, Joe, is that, based on non-clinical studies, we know the therapeutic window actually goes pretty low. So, we know that in the single digit range, we would see efficacy based on what we're seeing in the animal. So it gives us confidence that we could stay low and still get the potency, right, there's a therapeutic effect, we would expect.
What we know so far is among the patients that got the lower doses early in the course, there's only a few patients, they didn't seem to have the problem at all. And in fact, their lower extremities were improving prior to the event. So not only were they not having an adverse effect, their actually lower extremity function was actually one of the first things that people were talking about, that they weren't falling down, they're able to walk uphill, they're walking on grass, and not falling down. These kids fall down a lot.
So when they stop falling down parents notice, right, because it's kind of normal for them. So we think that those early dose we're seeing an improvement even before the effects. So I think that's why we're pretty confident that lower extremity effects not happening at lower doses, because they wouldn't be getting better if you're having a safety event at the lower doses.
So the combination of those two features I think put us in position to believe that lower doses will get the safety and appropriate menstruation. And we believe the Trendelenburg flush approach we're taking ex-U.S. will optimize the delivery of drug and make sure it's not sitting down at a high concentration locally, causing a chemical effect.
Got it. Thank you.
And your last question is from Joon Lee with Truist Securities. Your line is open.
Thanks for taking the follow-up question. So just to clarify Emil, you said that you saw no antibodies, or cells implying that it's unlikely to be an adaptive immune reaction, which sort of a sewage is FDA is concerned on the dosing. But have you ruled out the formation of any like tertiary structures or like self-complimentary of their GTX-102 that may trigger innate immune responses? Because just curious what sources of that XP [ph] what FDA may be worried about? So, thank you.
Yeah. Thank you. From everything we value, the only thing we're seeing is like, localized inflammation, there's nothing systemic. So any structure thing you're talking about, wouldn't necessarily just become a localized phenomenon. It should have been systemic because the drug gets absorbed, we can prove it to you, it's absorbed in the circulation at significant concentrations and is going -- as from the animal says, land up in the kidney and everywhere. So why would you have such a highly localized effect if you're really having this fundamental problem? So, I really don't think there's anything about it that fits that story. And we’ve done a lot of work on innate immunity and otherwise.
Actually, I agree with you, because you don't see any effect in the brain itself, it's just local. So it's not like you see it wherever the end of [indiscernible] goes.
Right, you only see it where the first place is applied. So it's why it's a very concentration dependent. If it was a nucleotide targeting thing, which we by the way, they did some detailed work on showing it does not, but if it were, it shouldn't be happening wherever the drug is. It doesn't. It is highly localized to just below T-12 to L-5 that area, not even up the cord where you know the drug went there. So you wouldn't see such a weird localized phenomenon, I think.
That's why, I think, if you look at a lot of the data, the [indiscernible] cause a nonspecific toxicity thing. That's what this looks like to me. And it's concentration dependent, so we just need to stay below the threshold. And we'll get it. The specificity part is very potent. We just need to keep the other part managed.
Thanks for the follow-up. Thank you.
Great.
And that concludes the Q&A session for this conference call. I will now turn the call back to Joshua Higa for additional or closing remarks.
Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at ir@ultragenyx.com. Thank you for joining us.
Ladies and gentlemen, this concludes today's conference call. You may now disconnect. Stay safe and well. Have a good day.