Q2 2023 Ultragenyx Pharmaceutical Inc Earnings Call
Good afternoon, and welcome to the Altra Genic second quarter 2023 financial results Conference call. At this time all participants are in a listen only mode. At the end of the prepared remarks, you'll have the opportunity to ask a question during the Q&A portion of the call. It is now my pleasure to turn the call over to Joshua <unk>, Vice President of Investor Relations.
Thank you we have issued a press release detailing our financial results, which you can find on our website ultra gannett's dot com joining.
Joining me on this call our aim of crackers, Chief Executive Officer, President, Eric Harris, Chief Commercial Officer, Eric Crumbles, Chief Medical Officer, Eric Olson Senior Vice President of corporate strategy, and finance and tax anger, Chief accounting officer, I'd like to remind everyone that during today's call, we'll be making forward looking statements.
These statements are subject to certain risks and uncertainties and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings and now I'll turn the call over to him.
Thanks, Josh and good afternoon, everyone.
It has been a year of increasing momentum marked by advances in our lead clinical programs, which we expect to result in multiple important data catalysts over the next few quarters.
Same time, our excellent commercial efforts continue to drive meaningful revenue growth across the portfolio.
<unk> revenue in North America, with our partner Kyowa, Kirin, and then Latin America as well.
I'll spend a few minutes discussing the Oscars imperfect and Angelman syndrome programs before turning the call over to Erik Harris to talk through our commercial update.
Beginning with O I.
In June we reported exciting data from the phase two dose finding portion of the pivotal orbit study showing statistically significant increase in levels of serum P. One N P. A sensitive marker bone formation.
The Boeing production responses patients was extraordinary this.
Led to a rapid bone building effect following just three months of treatment to treat the mab, resulting in nearly 10% increase in lumbar bone marrow density.
At baseline these patients had very limited bone marrow density with an average Z score in the 20th cohort of minus 2.12, which means the bone mineral density with two standard deviations below the mean of normal patients for their age.
After three months on therapy that means the score increased by plus six five points resolving nearly one third of the deficit from normal in a relatively short period of time.
As we've said before patients are showing meaningful improvements in bone health and we are highly encouraged with how theyre doing.
Improved bone health refers to the incidence of fractures bone pain and relative global health activity the patients.
In the ongoing phase two we continue to collect data compare fracture frequency during the conduct of the study to show the impact of the truth of the map and increase the bummer density on fracture rates.
To share this data at an analyst day in mid October around the time of the ASB Emaar the major bone focused meeting.
In July we announced that we initiated dosing patients in two phase III studies of <unk> mab into different age groups.
The phase II portion of the pivotal orbit studies are valid and the effect of Skus map compared to placebo on annualized clinical fracture rate in patients, 5% to 25 years old.
Newly initiated phase III Cosmic studies and active controlled study evaluates the truth of the mab compared to IV <unk> phosphate therapy, an annualized total fracture eight in patients aged two to five years old.
Enrollment both of these studies is going well so far in part because of the phase two data has generated a lot of excitement for the potential to treat <unk> for both the clinical sites and from the patient community.
Moving to our Angelman program in.
In May we announced we received FDA agreement to expand the ongoing global phase one two trial with Gtx 102 to patient with Angelman syndrome in the U S.
The protocol amendment enabled us to harmonize the dosing range of used between the U S and ex U S cohorts of the study.
Since then we've been working to activate U S sites that had been on hold for a couple of years.
<unk> actively enrolling the expansion cohort globally.
Enrollment in expansion cohorts is going well, particularly over the last couple of months.
Through today, we've enrolled more than 20 patients.
While we are on track to have a patient with a full six months data by the end of the year. We've noted that waiting just a few more months will enable us to report a more substantial update on well more than 20 patients with six months of clinical data plus safety data on all enrolled.
Trial is going well it seems more prudent to wait for this larger set of expansion cohort data, which we expect to have in the middle of the first half of 2024 based on enrolled patients to date.
We will also provide management program updated analyst day event in mid October . This is an opportunity for us to provide more context for the clinical meaningfulness of the changes that have been observed in the study.
Now I will turn the call over to Eric Eric to provide an update on our commercial efforts for the first quarter.
Okay.
Thank you Emil and good afternoon, everyone.
On April 27, 2023, five years. After we began our highly successful Chris feeder commercialization efforts with.
We transitioned in North America commercialization responsibilities to our partner Kyowa Kirin.
In the second quarter 2023.
Combined teams in the U S continued to generate new start forms.
And are providing continuity of care for the existing patients.
Our close collaboration and planning for the transition over the past two years.
Has resulted in a seamless transition.
Continued revenue growth.
And importantly, minimize the impact on patients and their providers.
As a reminder, a smaller ultra <unk> commercial team will remain in place supporting the proceed of program in the U S.
Alongside their counter AKC counterparts through April 2024.
Even beyond that time <unk> will continue to retain that responsibilities to promote proceed to medical geneticists and North America.
We are thankful for the successful collaboration and expect to continue expanding penetration in the adult and pediatric markets.
Shifting to Christina in Latin America.
The team has continued to build impressive momentum in the region as of June 30.
There were approximately 410 patients on reimbursed therapy.
Which includes approximately 65, new patients who began commercial therapy in the quarter.
Latin America is beginning to approach the same rate of commercial patient accrual as we saw last year in the U S, which bodes well for the long term potential in the region.
Each country has its own process to obtain regulatory and reimbursement approval.
But our team has been diligently working to facilitate broad access to <unk>. Despite the hurdles.
I expect the underlying demand for Christina in Latin America to continue growing at a steady rate and becoming an increasingly greater contributor to the ultra <unk> commercial story.
Today, we are reaffirming the Chris feeder guidance, we issued at the beginning of the year.
The range of $325 million to $340 million includes all regions and all forms of <unk> revenue.
More specifically it includes for speed of product revenue from Latin America, and Turkey, the cash and noncash royalties from North America and Europe .
And the collaboration profit share revenue prior to the transition.
I'll now turn to Dolby and began in North America.
In the second quarter, we modestly expanded the U S that youll be commercial team with season.
Personnel from our crispy the team to support continued growth and adoption of <unk>.
During the first half of 2023, we added 61 completed start forms. We also increased reimbursements 254 reimburse patients in the first half of 2023.
We continue to expand the number of treatise of <unk>, adding 18, new prescribers, including some health care professionals and centers for neuromuscular medicine.
In Canada, we continue to make steady progress following the positive opinion, we received from Canada complete.
Completing pan CPA pricing negotiations and signing prevention all.
Listing agreements.
And Latin America, we are continuing to leverage our existing infrastructure to commercialize the jewelry the patient finding efforts have generated a growing number of patients with a confirmed diagnosis across Argentina, Brazil, Mexico and Colombia.
We are continuing to work with the authorities across the region to ensure <unk> is available for all patients who could benefit from this therapy.
Across Europe , we continue to deepen awareness of LC <unk> with key stakeholders and address the high unmet need through named patient and early access programs requests are coming from all across all major European markets as well as Greece, Israel and the Middle East.
We continue to expect 2023 global <unk> revenue to be between 65 and $75 million REO.
Reaffirming the range, we announced at the beginning of the year.
Lastly, I'd like to touch on Ftes at the team is focused on unlocking access across all markets in the EMEA region deepening the awareness of HOS H and the urgency to treat and reinforcing <unk> unique profile amongst stakeholders occur.
Across the region, a steady growing number of patients are gaining access to <unk> through various early access programs. We are on track to launch in certain key EU markets over the next six months and our field teams are preparing the market accordingly.
Outside of the U S. We are continuing to prepare for launches in Canada, Japan and other major markets around the world.
Further expanding global access to this important therapy.
Across all regions, we have received overwhelmingly positive feedback for our Keystone from Kols and patients and they have continued to highlight the significant unmet need for this treatment.
Our teams will continue in their efforts to bring this product to people living with HOS rates as quickly as possible.
In closing we are reaffirming our 2023 total revenue guidance range issued at the beginning of the year of $425 million to $450 million.
With that I'll turn the call to Eric to share more details on our financial results for the quarter.
Thanks, Eric.
Earlier today, we issued a press release <unk> financial results for the quarter, which I will briefly summarize.
Company revenue for the quarter ended June 32023 totaled $108 million.
Because we had a revenue for the quarter was $83 million, which includes $61 million from North America 16 million from Latin America, and $6 million in European royalty and other product revenue.
Because we had a revenue figures for North America, and Europe are inclusive of noncash components as a result of our previous royalty financings.
As we typically remind you ordering patterns in Latin America can fluctuate quarter to quarter, we are continuing to see significant growth in the underlying demand for <unk>.
The jewelry revenue for the quarter was $16 million with continued strong north American demand driving 22% growth versus the second quarter of 2022.
<unk> revenue for the same time period was $8 million.
It's worth noting that <unk> revenue maintained the same level, we saw in the first quarter, largely driven by new patients in Brazil, and strong ordering from the U S.
Even six years after launch this ultra rare product continues to grow and patient accrual and geographic reach.
Our total operating expenses for the quarter ended June 32023, or $256 million, which includes R&D expenses of $165 million SG&A expenses of $81 million and cost of sales of $10 million.
Operating expenses for the quarter include noncash stock based compensation of $35 million and a one time milestone of 9 million payable tomorrow upon initiation of the phase III orbit study.
Hi.
For the second quarter of 2023, net loss was $160 million or $2 25 per share.
We ended the quarter with approximately $618 million in cash cash equivalents and marketable securities.
As expected through the first half of the year cash used in operations was disproportionately greater than what we expect in the second half of the year.
This is primarily driven by the timing of annual bonus payments and changes in certain working capital accounts.
<unk>, we expect operating expenses to decrease in the second half of the year driven by realized cost efficiencies and substantially reduced because we had in North America commercial expenses with the conclusion of the profit share period in April .
With the impact of these cost reductions projected second half revenue growth and the timing of the working capital changes previously mentioned, we expect 2023 net cash using operations to be around $400 million.
Now I'll turn the call to our CMO, Eric <unk>, who will provide an update on our key clinical programs.
Erin and good afternoon, everyone Haynesville has already discussed the progress in the quarter for the osteogenesis imperfecta in Angelman programs. So I'll briefly touch on our latest progress and our gene therapy pipeline Star.
Starting with <unk> 701 for the potential treatment of Wilson disease.
Earlier this week, we announced that we have begun dosing the second dose escalation cohort in our pivotal study following completion of dosing and data review from the first cohort.
In this first stage of the pivotal study we are evaluating the safety and efficacy of up to three dose levels to determine the dose for the second stage of the study that will support registration.
In July the data safety monitoring board agreed that it was safe to proceed with dosing patients at the higher dose of <unk> thousand 13.
It's our first patient in cohort two has already been dose and the other four patients have been identified.
This gene therapy is designed to directly address the underlying cause of disease by establishing the normal trafficking of copper. This will address both the toxicity of free copper and the copper deficiency.
Driving many of the signs and symptoms seen in patients who are not well manage on key leaders and the first dose cohort <unk> 701 has been well tolerated with no unexpected related treatment emergent adverse events observed as of July 11th and there are early signals of the establishment of normal trafficking.
Copper.
Initially study entry required well controlled signs and symptoms of Wilson disease on current standard of care.
Which proved challenging and resulted in a large number of screen failures as many patients for example, still have elevation in liver transaminase. Despite optimized key later in gene therapy.
This tells us that even with current standard of care there remains a real unmet need for these patients.
After additional discussions with regulatory authorities, we have changed the entry criteria enrollment has accelerated.
We are now on track to complete enrollment in stage one around the end of the year and expect to share initial data in the first half of 2024.
Moving to <unk> 401 for the potential treatment of glycogen storage disease type one.
It is important to remember that all patients in the phase one two study responded and showed meaningful reductions in their dependence on oral glucose replacement therapy <unk>.
These patients have demonstrated a durable response with patients moving into their fourth and fifth year of follow up with more detailed data presented at <unk> in may.
We have previously disclosed the phase III study was fully enrolled earlier in the year. We expect data from the 48 week primary analysis period to read out in the first half of 2024, we look forward to sharing the first phase III data generated by our gene therapy portfolio next year.
Quickly on <unk> 301.
For the potential treatment of OTC ornithine <unk> deficiency enrollment in the phase III study began earlier this year and this is a 64 week study that is designed to enroll approximately 50 patients we are gaining meaningful traction with recruitment of the study, especially as more health care providers and <unk>.
Patients appreciate the phase one two data with durable responses lasting more than five five years with more detailed data also presented at <unk> in may.
Currently there are 15 active global sites with additional site activation is pending regulatory and IRB feedback in Italy, U K, Japan, and Australia, we look forward to providing enrollment updates over the coming quarters. As this program continues to build momentum.
Now I'll turn the call back to Emil to highlight the key upcoming milestones and provide some closing remarks.
Thank you Eric I'll summarize the key upcoming clinical catalysts before we open up for Q&A.
Starting with <unk> 143 for US just superfecta enrollment in both of the phase III is going well supported by meaningful demand from patients.
Our goal is to have both of these studies fully enrolled around the end of the year.
We also plan to provide additional clinical data from the phase II portion set including fractionated at analyst day in mid October .
Next Gtx 102 in Angelman syndrome, we're planning to give an update on the program at the analyst day in mid October that would include some information about the treatment effects. We have observed so far in the earlier dose cohorts, we expect to share expansion data in the middle of the first half of 2024, when we're able to share six month data on at least 20 place.
<unk>.
Closing with our gene therapy program for <unk> several months will cease enrolling patients in the dose finding stage. We're excited about completing the first cohort and starting the second we expect this dose finding stage, we complete around the end of the year with data on safety initial efficacy spec in the first half of 2024.
TJ for one for GSD, one eight dose the last patient pivotal study earlier. This year. We're now in the 48 week window and expect to share. This phase III data in the first half of 2024.
Through the first half of the year, we've made meaningful progress across all of our priority initiatives. We finished and opened our gene therapy manufacturing facility outside of Boston and just week successful completed the first manufacturing run.
This is not a modular assembled plant or a furbished clean rooms, but the true ground up designed and built state of the art GMP manufacturing plant to build great plans hard but to do it during the pandemic to stay on time and on budget is exceptional and we give great kudos to our team on this accomplishment.
In the second quarter. The <unk> team continued to deliver meaningful revenue growth with the Latam casino franchise doing, particularly well, becoming a larger contributor to the company's financials.
Across the globe. Our development teams are advancing one of the largest late stage rare disease clinical pipelines in the industry and we expect to generate a number of important data class catalysts.
Over the next few quarters.
With that let's move on to your questions. Operator, please provide the Q&A instructions.
Thank you ladies and gentlemen, if you have a question or a comment at this time. Please press star one on your telephone. If your question has been answered or you wish to move yourself from the queue. Please press star one again and we also ask that you limit yourself to one question and one follow up one moment for our first question.
Our first question comes from Gena Wang with Barclays. Your line is open.
Thank you.
One quick question regarding the Angelman program.
October update.
Nickel measurement will you be.
Presenting and is Bailey.
A key measurement and if so what is your bar for efficacy.
To move forward.
Yes, so our plan with when we.
We will talk about their spokesman clinic liens of the effects we're seeing.
And the information on the Bally's and that comparison with something we will focus on with the expansion cohorts, where we have a large number of patients compared to a larger number of natural history patients to give you the kind of quantity maybe.
<unk> so the tober will focus more on the clinical meaningfulness and not so much on the detailed quantitative information, we'll reserve that for the expansion cohorts.
Okay, Amit listen maybe follow up a quick follow up questions. So based on the natural history, what will be the bally's see the change that you consider will be clinical meaningful that you would be looking for for your expansion cohort.
Well, we've already put forth that the size of change we've seen with our clinically meaningful so the mountain <unk> seen before is there I think.
I'd, rather not go deeper into it I think we need to do it in a more deeper context with data at hand, and I'd, rather not go deep into that discussion at this moment, but what we put out the bally data and we put out the other data we will have the clinically meaningful clinical meaningful thresholds quantitative way of the natural history data to look at.
And I would not folks only a daily IC Theres also other endpoints, we're going to be looking at because were still working through the data from our expansion cores to help us really nailed down what's the right answer and so still in the mix as the global impression scale CGI scores with Jeff. He has accepted primary which would allow you to cover more domains essentially.
<unk> and be more angelman specific.
So we're still looking at a number of those particular endpoints, but the truth is we've had relatively small amounts of data from these escalating cohorts expansion data is allows us to really get a large number of patients treated the same way and to give us.
Kind of quantitative to really answer your questions.
In a robust way, we're just not quite there yet, but I feel good about where we're at in the program and the fact that we have a drug that works and that we need to figure out how to move to the phase III.
Thank you.
One moment for our next question.
Okay.
Our next question comes from Lisa <unk> with Evercore ISI. Your line is open.
Hi, there can you just give us a sense of.
Your level of confidence about.
What youre seeing in the <unk>.
<unk> program and how that changes in bone mineral density.
Right.
Two potential changes you might see in fracture.
Yes, we are.
Have a high level of confidence that the magnitude of a bogo events. We saw at three months was already sufficient enough to improve straight bonds are probably reduced fractures at that level. We saw at three months in.
So we have high confidence in fact that memorial density when improved.
By this mechanism and Tesco Asda mechanism, where youre getting anabolism or produce production a new bone.
We will translate into fracture improvements.
We've talked about the non clinical data in the past, but we will be able to talk more about this at the October analyst day to provide that support but we have a high level of confidence that the BMD produced by <unk> will translate into fracture reduction.
Just as a follow up on that.
Can you explain to me the amount of sort of the bone mineral density levels of ally patients how does it relate to those hubs.
<unk> patients because I'm, just trying to kind of relate that to changes in the amount of changes you're seeing to what outcomes and seen in osteoporosis and it seems to me maybe at that.
Mel density levels are slightly different could you can you expand on that at all.
Sure Lisa what we said for this population. This study is that the mean pulmonary density was minus $2, one two which means to scan. It relates both to mean abnormal people now osteoporosis patients have reduced a bubble of density I don't have for you exact comparisons to put forth, but I would say that.
Mean, a minus two <unk> is pretty low on the bone scale and if you look at the range, we had patients as low as minus four and aviation. So these patients have I think a more severe on average borrowed density problem that on average our osteoporosis patient wood and therefore have more need of bone.
<unk> what has been the Miss the misunderstanding is everyone thought that the defect and the Colosseum was why the bonds or fracturing, what we're kind of trying to say is actually while that may be a factor is in fact, the effect of that mutation on both production appears to be a bigger factor.
And that's something we can change with <unk> and Thats why we think we're going to have an important effect on oi.
Thanks.
Our next question comes from Maury Raycroft with Jefferies. Your line is open.
Hi, Thanks for taking my question.
Based on the expansion data in first half 'twenty four is the timeline for the pivotal study starts shifted out some and have you received any preliminary feedback from regulators on your data so far and what the pivotal design and endpoint could be and is this something we can learn more about in the mid October update.
Yes, I don't think actually the timeline changes the timeline for the phase III is going to be but there's going to be setting up the protocol in the planet endpoint.
Even before the full data are available. So we will already have understood. What's going on we will have our discussions with the FDA soon after that and have a full protocol ready to get kick in and got going in 'twenty. Four so it doesn't really change that timeline. It teams change the timeline of how much we know.
When but we are going to be gaining ground during the year and we expect to talk with the clinical outcome group at FDA The Colo group.
This year, we Havent talked further yet with the FDA were looking at when we want to get to them. They said we could go to them. We'll look at when we want to start talking to them about endpoints. They appreciate that this will require a lot more discussion.
Then an average program being a first ever in a very complex developmental disorder, but.
The first meeting with color, we will get some ideas and feedback we.
We will gain our data as we go along this year, but.
I would expect.
Late in the year early next year, we'll have a handle on what we think the endpoints will be the data. We will then further finalize the decision on dose regimen and allow us to head and then the phase II meeting.
In the first half is our expectation and to think about getting to a phase III study that next year.
Got it that's helpful. Thanks for taking my questions.
Our next question comes from Joseph Schwartz with Leerink Partners. Your line is open.
Hi, I'm Jerry dialing in for Joe. Thank you for taking our question I have two on <unk>.
701 for Wilson disease.
Could you talk about your decision to move John Open label business line and broadening inclusion criteria in phase one how do these two factors impact the efficacy results if any and.
If any that we're going to get from the data that we're going to get in the first half of 'twenty four and secondly, I believe in your opening remarks, you mentioned timelines around cohort cue.
Mccourt to Lee when can we expect the stage one cohort three patients can be dose than cohort.
Cohort three data will be included in the update provided in one half.
Okay.
Sure well I'll start with the last part is our expectation when we talk about first half is to is to talk include cohort three patients and the point at that point, we'd make a decision on dose and to then kick off enrollment in phase III because it's a combination study we go right to phase III, we make the call make the decision and move so the beauty of that is a cut out any debt.
Time, it's already agreed on the endpoints and moving forward, but let me, let Eric crime Beth talked through the open label and the criteria changes and the reason for those.
The conduct of the study.
No I think in the context of a single site.
Registration, it's always tempting at the beginning to kind of go towards double blind.
Format, there, but the truth is we do want to learn and that initial stage, there and the blinding or is it really kind of a hindering that so that was in large part the driver to moving to open label and I think it was absolutely so.
The rate decision.
<unk> the data and really looking at those early signals after the readout from our first cohort.
And as far as entry criteria.
A gene therapy has never been studied enrolling patients and certainly it makes good sense to want to put any liver directed gene therapy into as healthy of liver as possible.
A lot of traders out there would say their patients are very good there team is good and does a very good job of managing the patients.
Truth is once we started screening a large number of patients we realized most of these patients do not have <unk> in the normal range, meaning that they are still really having effect on the liver from the toxicity of that free copper.
But we needed to collect that data and have that discussion with the agency in order to adjust those entry criteria to allow more patients to enter the study.
Okay.
Okay got it thank you.
Our next question comes from Eagle Chavez with Citigroup. Your line is open.
Yes, hi, thanks. Another one on 701 I think you mentioned you are seeing early signals of a normal traffic on copper can you expand on that a little bit is the goal of this gene therapy to get patients back into the normal range of copper are just closer to normal range. Thank you.
It's a little bit early I'll, let Eric comment a little more on that but it's a little bit early to go deep into the data since just the first cohort, but the goal of the program certainly was to try to improve copper distribution sufficiently to remove copper deficiency, which we believe is occurring.
In not fully understood.
In many patients and so yes, we havent set a threshold requirement for how much that would be but our goal is by having both detoxification and some improvement distribution. We think we can have a much bigger impact with U K, which escalation. So maybe you want to talk about the early signals of copper right and I think that's really the point here I mean.
Key leaders have been great for those patient population, but key leaders.
Buying copper.
Freely in circulation.
You are not pulling copper out of these hepatocytes for its accumulating so again that the fact that you have elevated transaminase says.
<unk>.
Youre not excrete copper into the bile and you're not loading copper onto ceruloplasmin, which is how it traffics to silos for the for copper to act as an important co factor for a lot of enzymes. So when you look at how you are measuring koppers for our key later, it's different than how we're looking at copper.
Levels, whether it's here in bladder from whatever capacity once you establish normal traffic patterns and then importantly, we are still are looking in activity based assay, which shows the loading of copper onto ceruloplasmin. So really a very direct measure of the effect of this gene therapy.
Yes. So the trapping is we have direct measures near where they are looking at to give us that sense, which is what the description of improving copper trafficking to come from but.
But it's early yet as cohort one we have more to go.
Thanks, <unk> and Eric and then.
And gentlemen, just operationally can you comment.
<unk> in October and then for the one next year, how many of these patients under the U S protocol are going to be represented in each of those updates just ballpark.
Well you see.
In October most of the patients are in the program are ex U S is only a small number that were on to Mig there now shifting to a higher dose cohort E.
So it's a relatively small number of U S patients are involved in that.
The exact number I don't think it was worth knowing we put it in the data release, how many patients we have but.
I think what we've what's probably most support as we talk about expansion, we're seeing we're well more than 20, it will be significantly more in 'twenty that will have six months of data. So that's why we can do a little more statistical analysis.
Have a group of people all treated the same way where it is in the <unk>.
Nation cohorts are treated different ways different doses.
Not as easy to to annualize so there'll be a small number of U S patients in the fall but.
A larger number.
<unk> loaded the correct way that will be represented in the.
First half update on the expansion cohorts.
Okay. Thank you.
Our next question comes from Dae Gon Ha with Stifel. Your line is open.
Just two from me as well one a commercial question just wanted to clarify what the revenue number is it seems like there was a jump in the EU derive royalty.
Misunderstanding something or can you maybe delve into what happened there and what the rest of the year might look like from the EU side of things and then second on the clinical side. So looking at the press release on Gtx 102, you mentioned, the encouraging dose and time dependent clinical activity.
I was wondering if you can speak to any inter patient variability here is there a certain duration of follow up or certain doses that you are starting to converge on for driving therapeutic benefit or is it still very much individualized. Thanks, so much.
Great well I'll start with the second part and then either Eric or Eric can talk about the EU part.
So.
What we said is that as we look through time and we even published some of that prevented some of the day in July that that the day 128 data is not as strong as it is a day 170 that going a little longer, particularly some patients have a significant improvement in that timeframe. There is no doubt there is some variation between patients responsiveness some reversal.
<unk> are at very low doses, some need higher doses and that will be true no matter, what our goal and the expansion of course is not to find the perfect dose for all patients with defined a very good dose that gives a good effect a large number of patients, but our expectation long run is that there may be some need to be individualization and titration.
And it's just hard to run that in a phase III program. So the main goal of expansion to find a dose that works. The majority of patients that works well and we think we can we can do that we see changes in all patients all of them have improvements, but there's definitely some variation the degrees of sensitivity and we're still learning more.
And truth is we've created relatively small numbers of patients now for a year. It's about I think it's more in the 13 that have a year or so.
And with the expansion cohorts as can allow us to get.
40 patients on drug and really learn something about.
At 40 patients treated the same way and get a better handle on the range and sensitivity, but our expectation a little always be some variation and we'll manage it but I think if we can get a majority of patients having a good treatment effect a significant transform or change of life, then we'll be able to manage an extension getting to the right optimal.
So let me leave with that.
Erin.
About the EU on the EU the noncash royalty did not jump in Q2, but as a reminder, there is a part of our North America royalty that is noncash now.
And we can follow up offline with any other questions.
Thanks, Kevin lets move onto the next question. Please our next question is from Juran Weber with TD Cowen Your line is open.
Great. Thanks for taking my question.
So I got two one just on Angelman in the study how many patients do you think you want to have in phase two.
Those nailed down the powering for the phase III.
And secondly, and potentially the nail down the schedule the dosing schedule and then secondly on sanfilippo.
The program to gene therapy program that Youre license.
Based on the phase one phase two data is there any way you can file for accelerated approval, just given fda's, new overture, an accelerated pathway, even though that data.
It's still early not perfect while youre doing the phase III confirmatory. Thank you.
Thank you Eric So on the Asian program, we do have a lot of patients from the extension that are on drug for a long time. So that's a chunk of patients that help us deciding the phase III.
We will announce in the mid part of first half data from at least 20, it'll be well more than 20%.
Of data, we would expect to have 40, plus enrolled maybe even closer to 50 enrolled and so by.
Second quarter. So we'll have a lot of data on all of those patients that will help contribute to the final decisions on dosing regimen that will be making hopefully that gives you kind of an outline of how much data. We expect to have we definitely thank you need more than a handful to make this kind of decision 20, or so 20 plus.
We'll be a good number to make.
To handle what we have but before we actually pull the trigger on the phase III. We expect to have 40 patients worth of data or more to be confident that we've got the dose exactly right and we're picking the right things and.
So in Sanfilippo syndrome, sorry approvals near Dear in my heart.
Fighting for inborn areas for.
Nearly 30 years read my book David Brian .
Anyways.
The truth is that the FDA.
Once in particularly Peter marks wants us to do because our approval, but it's hard to get reviewers kind of degree we are working with the FDA potentially on a workshop to talk about that.
What I would say to you is on the our own sampling program, it's not exactly the license I guess it was licensed but it was handed off to us.
And we're excited to help these patients get four we did have to put into play.
The CMC part of the story of making the product has to get made and a lot of the timely is driven more about getting CMC setup than the actual data at par so.
In the end of the day.
Yes.
Even if they said today that we could file we're still not ready because the CMC part so, but we're going to work on getting site approval I do believe there is.
And appreciation, but we know we need to get them degrees of science and start doing it and we're setting up for the group companies to go to the FDA have a workshop and talk through that and I've been advocating the FDA both in editorials and in meetings about the need to start seeing the science differently and we hope we can get that to.
<unk> I think if we can get that to happen for sanfilippo and other MTS disorders. It opens the door to us actually getting the benefit of precision medicines that we have trouble fully capturing today with a system. That's just not designed for a rare complex neurologic diseases needing treatment.
Thank you. Our next question comes from Joon Lee with TD, sorry tourist Securities. Your line is open.
For taking our questions I have a couple on such as map, what's the value of doing an active comparator study against IV.
IV is softening, which is off label are you looking for non inferiority or superiority and hydrogen powered the study and Gtx 102 in light of the recent discontinuation will the nurse then what gives you confidence that one or two can succeed in.
Angelman, where within nursing with all the resources that most has to offer sales advance. Thank you.
Sure so.
On <unk>, our original plan was due to the placebo controlled trial is the gold standard with without an approved therapy. The truth is they're really young patients. There was more concern that those patients who have very high fracs rates couldnt be at a placebo and there was resistant to that.
At the same time people are using off label Bisphosphonates and people have impression of them as being standard of care, even though it's off label.
So our view, though is that the protective effects of truth that should be far better far superior to bisphosphonates, but the best way to get that is actually steady it improve it with Bisphosphonates five Grand in my studies have been completed three failed two succeeded the treatment effect size is of 'twenty.
8% reduction.
In fractures. So it's not very much patients do seem to feel better with it was which is why it is being used.
In our trial, we are planning to do superiority of <unk> math to Bisphosphonates and we think the high fracture right now.
In that population and our expected effect on those fractures should.
Should generate a successful study that.
Throughout the World all global areas, where there may be reimbursement question Bill to show Us <unk> should be standard of care for Oi and not just the second line treatment.
That's what that study we will do it also particularly important in Europe , where comparison to.
Drugs are being used is important part of getting good reimbursement. So there's a number of factors and all of that on the on the GTA for two and Roche Reuven Harrison termination, we have been saying from the beginning that.
There are many ways to go after the Haynesville locus, but the locus specific region that we're working on is more potent and it's because it's near the five prime end of the message is the work that Dr. <unk> had Roche and <unk> are working further downstream when we've made those molecules we do not feel there is potent.
The only data comparison was at Roche required 24 milligrams to do what we're doing with one or two milligram.
I think whatever happened to trial, we don't know, we only know with public but they werent able to achieve a dose level.
Applied safely that will allow them to get their knockdown they required achieve with their particular goals, where but in my view that was somewhat expected because I think <unk> was not enough and I don't think its speaks at all to the mechanism, which we know from our data and our own hands.
We're having a.
Transform effect on Angelman patients and one that I think will be extremely important to them.
And that's the operating at the dose ranges of 5% to 14 milligrams.
So that is what I think I think it shows wide science matters, and sometimes one really smart guy can beat a company with large amounts of money.
Thanks Amy.
Our next question comes from <unk> Richter with Goldman Sachs. Your line is open.
We're taking our question. This is Tommy on for Sullivan, just trying to understand maybe where the format of the Angelman release at the analyst day is it going to be in a similar kind of presentation is for instance, the update last year and any more detail you can provide on follow up for patient numbers and just if you have any updates on how the OTC phase III on raw.
<unk> is progressing thank you.
Sure I'll start with Angelman, and maybe Eric can comment on OTC enrollment.
So.
Essentially asphalt with the releases will look like yet you're one of the categories. The size of the treatment effects, we all want to know.
It's not going to be the same as July .
In July we put out a lot of raw information, which we were personally quite excited about at the company and that we received we had.
Had a complex response from investors because it wasn't well the adjusted what we're talking about announced is not like that situation, where theres a lot of granular data is going to be more high level is going to talk about clinical meaningful information that will provide the help give people a better feel why we as a company are confident on the import.
So the therapy.
But it will not be focused on the quantitative data, which we've said would be.
We will let drive the expansion cohorts the large amounts of data to be able to do what I would call. The the data driven statistical kind of look at what we're seeing.
Alright, so its a little bit more about clinical meaningfulness and it'll be higher level than what we saw last July .
Presenting for OTC is likely to come in and it's doing really well.
Again designed very similar Lee with a similar global footprint with clinical trial sites to GST one area. So that truly global phase III study in there so.
Really good enrollment rate.
Really tracking well to.
Finish up enrollment next year.
Thanks next question please.
Our next question comes from Christopher Raymond with Piper Sandler Your line is open.
Hi, This is Nick broker breast Kieran for Chris Thanks for taking the question.
Just going back to the Wilson program I'm, sorry, if I missed this but I guess I was wondering if you could just expand on the changes you made for the patient inclusion criteria in the current study and I guess, we're just primarily around baseline liver chain diminished level.
Levels that were modified.
And then I guess just beyond this does this change your thinking at all about the potential addressable patient population for gene therapy.
So yes, so the two big parts of entry criteria that changed where are they all tiers.
After initial conversations with the FDA really wanting developed he is very close to the normal range.
With patients not being able to achieve that in <unk>, we were able to have that conversation and allow patients with with somewhat I would say mildly elevated atlas tiers and that was important.
And then also stability of copper levels on key later as in zinc.
I think most people would tell you that those are those are relatively stable on a user control. It turns out they are not so.
So quite a quite a bit of variability in copper levels, regardless of where you are looking so then again really changing that criteria.
Allow.
Enrollments are to really accelerate I would say we've always.
Have high expectations for this gene therapy, we do think with all of really kind of how we target to use diseases.
Replacing what's missing is important here key leaders have done a great job for these patients, but again, we want to affect both the toxicity of free copper, which <unk> done a decent job of addressing but then again with the signs and symptoms of patients who are not well managed John on key layers. We think is really.
Driven by the fact that copper is not able to traffic to cells and tissues that need copper doctors.
As a co factor for some important enzymes. So again addressing both parts of this disease and I think yes.
Really broadly applicable to.
All patients living with Wilson disease.
I would add that I think our view of the dress market has gone up we used to say it was a <unk>.
Fraction that might have severe disease, not manage our key layers.
Alexia on AZ key later also has been pulled because it really wasn't helping that that probably opens up the addressable market. Because there is some view that maybe that key later would be better but it wasn't giving.
Given our knowledge of how many people have transaminase and copper issues still feel right.
Do you think the addressable market for Wilson could be higher if we see.
Great effects copper distribution and symptom improvement otherwise I think theres, possibly that turns out to be.
More important player Wilson, a bigger fraction of the population, we still have more data to collect we're not there yet, but I do think the possibility that this could become a more important and major that all most or all patients who wilson could be addressable I think its a possibility which I think.
It makes us.
Really important program to push ahead as we are.
Great. Thank you.
Our next question comes from Kristen <unk> with Cantor Fitzgerald. Your line is open.
Everyone. Thanks for taking my question just one on manufacturing given the size of your new facility how much flexibility does this allow you to expand beyond the current pipeline and maybe what are some of the mid to longer term goals with building. This as well. Thank you.
Yes, the plant gives us a lot more flexibility because we can flip the switch what we do we're still in the buildup phase in terms of how many runs we can run but that will that will accelerate quickly and.
We also have a second suite that we can outfit and operate which would get us to be running 32 runs a year.
So I think.
We probably would have capacity to do for example, if we did partnerships or other deals we could offer manufacturing plus the piece of those type of deals.
It's something we could do but I would say to you we have really one of the larger AAV.
But <unk>.
Programs out there with three programs in phase III Wilson OTC GSD, one eight plus.
We also have potential to put in the plant the <unk> five <unk> deficiency.
Gene therapy, which is.
Heading to 90 and is actually the subject of the first run in the plant.
We also have a program to talk about too often in the Duchenne program, which is coming.
And potentially some others. So we have a great use for the plant, but I do think it gives us the capacity to be able to do some other manufacturing for other programs as needed.
And I think the team will be a superb team and given the challenges at <unk> I think that it will become a valuable asset broader than simply making our own products.
Thank you.
Our next question comes from <unk> with Jpmorgan. Your line is open.
Hi, everyone. This is <unk> on Friday, we just have one quick question will the analyst day, we only focus on the one three and Gtx, one thing or two programs or will the overall pipeline also have other various updates. Thank you.
Yes, our expectation is to have several other programs highlighted there.
Some you know about may be some you don't.
Could be interesting don't Miss it so.
We have.
Great pipeline the hard part is that it's really hard for most people to handle more than one or two good things, but <unk> got half a dozen things that we will have more of the gtx 102 or at the at the meeting so I think it tended to be exciting we tend to bring.
What we are learning new things, we've put together and hopefully give people better breadth of understanding of the value, we're creating and what we can do as a company is I think we will become the leading rare disease company out there.
Thank you. Our next question comes from Joel Beatty with Baird. Your line is open.
Hi, This is Ben on for Joel Thanks for taking the question.
I'm, sorry, if I missed it but what are next steps for dosing the remaining four patients in cohort two for Wilson disease.
Okay.
Yes, no. So we do have.
Two week dosing interval that was required by the FDA for cohort two of those additional four patients are aligned up and ready to go.
They're all screen in waiting so it's just a time clock now.
Yes, and then we will have another day SMB meeting and then we're going to be required to have a single week between dosing for the third cohort. So the timeline, we will start to accelerate.
Got it thank you so much.
And I'm not showing any further questions. This time I'd like to turn the call back over to Josh <unk> for any closing remarks.
Thank you. This concludes today's call. If there are any additional questions. Please contact us by phone or at IR at <unk> Dot com. Thank you for joining us.
Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful day.
Okay.
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Okay.
Okay.