Q3 2022 Ultragenyx Pharmaceutical Inc Earnings Call
Okay.
Thank you for standing by good afternoon, and welcome to the Altra Genies third quarter fiscal <unk>.
Financial results conference call at this time, all participants are in listen only mode. At the end of the prepared remarks, you will have the opportunity to ask questions. During the question and answer portion of the call. It is now my pleasure to turn the call over to Joshua Hager Executive director and head of Investor Relations.
Thank you.
A press release detailing our financial results, which you can find on our website at ultra <unk> Dot Com. Joining me on this call are <unk>, Chief Executive Officer, and President Eric Harris, Chief Commercial Officer, Marty Baird, Chief Financial Officer, and Camille Bedrosian, Chief Medical Officer, I'd like to remind everyone that during today's call we will be making.
<unk> 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 I will now turn the call over to Amy.
Thanks, Josh and good afternoon, everyone.
2022, it's been a year focused on execution for our team both commercially and in our pipeline.
So we've made substantive progress across our key priorities and initiatives despite ongoing macroeconomic challenges.
In the third quarter, we continued to achieve strong year over year growth from our commercial program.
Turning to broaden our commercial revenue base.
In Latin America, we are seeing positive commercial and regulatory momentum across multiple countries with increasing revenue.
In Europe , our launch with Keith is underway and we're seeing significant enthusiasm for lipid experts on the potential for <unk> to change the treatment paradigm.
With submitted already or will submit reimbursement dossiers in multiple countries and are beginning country specific pricing discussions.
We believe the enthusiasm of lipid extra from the project will help in supporting effective reimbursement discussions.
With regard to our pipeline, we acquired full control of the Gtx 102 program on promising science and the interim phase two data we shared in July continued to be encouraged by the progress of patients in the program and the safety profile with 10% to 12 mid dose is now being used in maintenance.
Over the next few months, we anticipate completing enrollment in the phase III study for <unk>, which has enrolled very well with the enthusiasm of patients for a new treatment option.
We also plan to complete enrollment of the phase III portion of the study for osteogenesis imperfecta in mid 2023, which should give us data on the bone biomarker response of two dose levels.
Last month I visit our gene therapy manufacturing facility outside of Boston with the <unk> Board of directors and were hosted by our team building the plant at.
It continued to be impressed with the quality of their work in fact have met or exceeded our timelines and maintain costs within budget for this greenfield project.
Despite the pandemic and global supply chain issues. The facility has remained on track to begin manufacturing operations next year, it should be a big boost to our gene therapy franchise.
We've also been focused on laying a solid financial foundation for the years ahead.
In July we raised $500 million with sale of a portion of our crispy the royalty and have established additional cost controls limiting head count operating expenses as well into 2023.
We believe we have the right team in place to achieve our priorities and we will actively manage our head count and spend while achieving these objectives.
Eric will provide more specifics on the commercial team's performance in the third quarter by wanted to briefly touch on our partnership with Kyowa Kirin.
We have worked closely with our partners throughout commercialization process to make receipt of a very successful rare disease launch.
We recently amended our collaboration agreement to allow both companies to be in the U S field for an extended period of time, ensuring US proceed a franchise will continue building on the solid solid foundations, we have established.
In the press release, we issued earlier today, we shared details of the amendment that increases our joint commercial effort for one year. After the transition of commercial responsibilities through April 2024.
Under the revised terms KN <unk> recently began field operations ahead of the transition and ultra JAKKS will maintain a consistent presence here in the U S for an additional full year until April 2024, after the transition to further increase field coverage.
Surge of additional average should help with identifying more escalation patients and providing them an opportunity to be treated and highlight each partner's commitments to maintaining continuity with the Cristina franchise.
During this time <unk> sales force expenses will continue to be shared with <unk>.
In addition objects will continue to call on medical genetics in North America. After that transition and then definitely based on the original terms of our collaboration agreement and will co lead the <unk> and Tio disease monitoring programs in partnership with <unk>.
Michael Jets are an important segment of health care providers, who treat pay.
Patients with <unk> and many of the disease are targeted by our other clinical stage programs.
With that I'll turn the call over to Eric to be more provide more specifics on our commercial performance for the quarter.
Thank you Emil and good afternoon, everyone I'll focus my section on the commercial team's efforts in the third quarter supporting Chris Vita.
<unk> and the upcoming launch of Ftes across Europe .
For <unk> within our profit share territory, we continue to see meaningful increases in key metrics, including the number of start forms.
Patients on reimbursed therapy and unique prescribers.
In the third quarter approximately 120 start forms were completed.
This is particularly impressive given the last time, we saw this type of increase in any given quarter was in early 2021.
These start forms have led to a steady increase in the number of reimbursed patients on therapy, driven by an ever expanding base of unique prescribers.
In the third quarter, approximately 60, new health care providers wrote a prescription for Chris fever.
We are well over four years into the launch of this rare disease product and I applaud. The team's continued efforts to find those community based physicians as we are increasingly finding more adults with community physicians.
Almost 50% of our new patients are now coming from new prescription writers, while the other 50% is coming from existing prescribers.
We are focused on increasing face to face activities and educating physicians as we come out of Covid and as many new offices are now open to seeing our field personnel.
While our team has been working closely with key our Karen for several years. The recently signed amendment allows us to work side by side in the field to ensure we can maximally support our patients during this transition.
The combination of additional <unk> sales specialists, beginning last month and the extension of our U S field team through April 2020, before enhances crispy, there's long term potential.
Outside of the profit share territory procedure was recently approved in Argentina for the treatment of <unk> in adults and children six months and older. This therapy is now approved in five countries in Latin America, including Argentina, Brazil, Chile.
Colombia and Mexico.
Brazil continues to be the largest market in Latin America, and while the uneven ordering patterns drive some well known quarter to quarter variability the underlying demand continues to grow at a steady pace.
Across all of our ultra <unk> regions, Chris Vita revenue in the first nine months of 2022 grew 34% compared to the same period of 2021.
We know the underlying demand is strong and supports our full year revenue forecast.
And we are reaffirming our 2020 to proceed our revenue guidance and ultrasonics territories of $250 million to $260 million.
Turning now to the Joey and beginning with the efforts in the U S. Many of the leading indicators, including number of start forms and patients on reimbursed therapy continued to exceed our expectations.
As of the third quarter. We have received approximately 400 completed start forms with over 340 patients on reimbursed therapy.
Since launch approximately 180 health care providers have written prescriptions for the Joey with.
With nearly half writing for more than one despite.
Despite these strong metrics there is an opportunity to continue educating healthcare providers on the benefits of optimal dose titration and supported by our clinical studies to assure patients are receiving an optimal dose.
Outside of the U S demand for <unk> continues to be led by named patient and early access programs in Europe , particularly in France and Italy.
In Latin America. The job is currently approved in Brazil, where we are continuing to work through the process to get full reimbursement approval.
In Mexico, We recently received orphan product recognition, which is similar to receiving approval with a few benefits that will enable us to get this important therapy to patients even faster.
While we continue to work to address the need for better dose titration for maximal effect in the U S. At this time, we are reaffirming the guidance range, we set at the beginning of the year.
$55 million to $65 million.
Clothes at closing briefly with <unk>, which we are preparing to launch in Europe , followed by Latin America, Canada, and Japan, where patients with clinically diagnosed homozygous familial hypercholesterolemia.
The data from Regeneron is pivotal study for <unk> were very impressive.
The drug demonstrated a significant improvement over standard of care with a 49% reduction in LDL C on top of all existing LDL lowering treatments.
The study also showed <unk> reduce ldlc by 72% in the most severe patients with less than 2% of LDL receptor activity feed.
Feedback from key opinion leaders is very positive, especially those who participated in the clinical studies and have seen the value of this novel mechanism of action for their patients. They understand the ftes of blocks and <unk> III, which enables a proven alternative pathway to convert <unk>.
<unk> into remnant cholesterol that can be easily cleared by the liver.
This bypasses the normal lipid metabolic process that leads to dangerously high levels of LDL C. In these patients.
Across Europe , we are in the process of filing reimbursement dossier and.
And look forward to beginning the country specific pricing discussions in parallel we are evaluating requests for named patient access which could generate the first orders later this year.
In summary, our global commercial team is delivering on our mission to being a leader in rare disease by ensuring access to Chris Vita.
<unk> <unk> and now <unk> to all patients who could benefit from these therapies with that I'll turn the call to Marty to share more details on the financial results for the quarter.
Great. Thanks, Eric.
Earlier today, we issued a press release that included financial results for the quarter, which I will briefly summarize.
Company revenue for the three months ended September 32022 totaled $90 7 million.
<unk> revenue in ultra <unk> territories were $64 5 million, including $51 3 million from the North American profit share territory, and net product sales of $13 2 million in other regions.
During the first nine months of the year. This included approximately $101 million stock based compensation $27 million of non-cash interest expense related to the royalty pharma and almost transactions and.
<unk> $21 million related to the decline in fair value of our equity investments in our tourists and solid bio.
These are offset by approximately $16 million of non-cash revenue related to the EU royalty.
We ended the quarter with approximately $1 billion in cash cash equivalents and marketable securities.
While we are well Capitalised. We are also continuing to make strategic operating decisions to manage our cash burn rate. As we have said 2022 is it peaks burn year for us as we have initiated multiple late stage clinical programs and license Keesa completed the acquisition of genetics and are completed in the build up.
A R gene therapy manufacturing facility.
As <unk> mentioned in the third quarter, we began the process of implementing initiatives that will limit head count and operating expenses as we head into 2023, while maintaining focus on our key value drivers with that I will now turn it over to Camille.
Thank you Marty and I to wish everyone. Good afternoon in the third quarter. We continued to advance one of the most diverse in late stage clinical pipelines and rare disease.
We also have made a number of strategic changes to our clinical studies that will enable faster enrollment as well as interim cuts of the data from our pivotal program.
Of the programs currently in the clinic I will briefly touch on Gtx, one O. Two phase one two for Angelman syndrome. The U X 143 phase 234, osteogenesis imperfecta and a few of the gene therapy program.
Starting with Gtx, one O two for Angelus syndrome, we continue to enroll in dose patients and the dose escalation cohorts of the phase one to study.
Thus far 13 patients have received a cumulative dose of at least 20 milligrams.
And 14 patients had had over 132 days of exposure to Gtx, one O two with no reported serious drug related safety events, including no reports of lower extremity weakness.
Crossing the threshold safely as important as the original five patients experienced lower extremity weakness at a minimum cumulative dose of 20 milligrams.
And and and exposure up to 132 days.
This continues to give us confidence that the amended dose administration strategy and slower titration may allow us to safely recreate efficacy seen in the original five patients.
We also have redose. The first two patients from the originally treated us cohort with at least two doses each in Canada include.
Including one that previously had a significant lower extremity weakness event.
These patients are doing well and there have been no reported serious drug related safety events, including no lower extremity weakness.
We are continuing to work through the process of aligning the U S and X U S protocol and intend to have clarity in the next few months.
We expect to begin enrollment in the expansion cohorts in the first half of 2023 and will provided data update once we have gathered substantial data from the cohort.
Turning now to you X 143, or <unk> for osteogenesis imperfecta.
The anti score Austin mechanism chosen that has the potential to reverse the majority of the bones Maladaptive response to college and mutation and strengthen bones substantially.
And we have a particularly strong belief in the value of this mechanism for patients with osteogenesis imperfecta.
For our ongoing so chosen that study we recently amended the pivotal phase two three protocol to remove placebo from the dose ranging phase II stage of this study to enable us to do real time analyses of the program.
We believe this change along with activating the last few sites will allow us to complete an enrollment of the 24 patients stage of this study in the next few months.
Data from this portion of the study are expected to be available in mid 2023, including the two months changes in bone biomarker response, they will establish the phase III dosing algorithm.
Concurrent with the day to read out we plan to transition to the larger randomized Street three portion of the study.
Moving to our gene therapy programs and starting with D. T X four O. One for the treatment of glycogen storage disease type one a which we are currently evaluating and a pivotal 48 week randomized double blind placebo controlled phase III study.
This program was recently granted prime designation from the European Medicines Medical authority or Ian a.
This designation provides opportunities for additional interactions with the agency and could lead to an accelerated approval pathway.
We'll call earlier this year, we focus resources on enrolling this study and these efforts have helped increase the rate of enrollment.
We currently anticipate completion of enrollment around the end of the year with phase III data approximately one year thereafter.
Turning now to you at seven O. One for Wilson disease, which continues to of all patients in the dose finding stage of the pivotal study.
Similar to you X 143, we recently removed the placebo from the stage of this study while.
While the protocol dictates a progressively shorter observation period between each patient we expect to complete enrollment of this stage in mid 2023 and plan to share data on safety and initial signs of clinical activity in late 2023 or early 2024.
The last program I mentioned in my prepared remarks is D. T X two O one for hemophilia a.
As part of a regular review buyer has decided to discontinue development of this program and return the rights to Orcher Jennings.
We continue to believe that this is a better version of he may gene therapy is in the right development hands.
We will not initiate further development of the checks to along without a partner, but we would be interested in a quality partner that has.
A clinical expertise and rare hematological disorders, and an interest in developing a high quality AAD He may therapy.
We will continue to monitor the hemophilia, a gene therapy landscape and explore our options with respect to potential partners.
With these updates I will now turn back the call to Emil Thank you.
Thank you Camille before we shifted accumulate portion of the call will provide a quick reminder of the upcoming milestones.
We expect the G F D. One a phase III to be fully enrolled around the end of the year based on how well it was rolling mill with the day to be shared approximately one year later.
For you, it's 143 and osteogenesis imperfecta, we expect a complete enrollment of the dose finding stage in the next few months unexpected sure phase two do transition to be three in mid 2023.
And Gtx, one or two in Angelman syndrome are highly encouraged by the progress of expect to begin rollman of large expansion cohorts in the first half of 2023.
Plan to provide a data update once we've gathered substantial data in 2023.
Lastly, you, it's a little oven for Sanfilippo syndrome, where continued Valerie bar, Mark and other data generated by Abu owner finalizing an approach to FTA regarding filing for approval based on this current data.
The scope of catalysts are commercial teams continue to execution field and the cost control measures Marty mentioned put us.
An actual position to deliver meaningful values of patients and shareholders.
With that let's move on to your questions. Operator, please provide the Q&A instructions.
Ladies and gentlemen.
The question that this time, please press star one on your telephone we ask that you. Please limit yourselves to one question and one follow ups you may get back in the queue. As time allows our first question comes from the line of June away from Barclays. Your question. Please.
Thank you for taking my question [laughter] I have a one regarding the enjoyment.
A press release, you said you were dozing any expansion cohort in first half 2023 does that mean the cost 67 showed.
<unk> sufficient CGI score improvements that you don't need to do.
Due to further dose escalation and also what will be the timing for next data update.
Yes, well, we're not now going to be commenting on the data from the dose escalation cohorts were just giving you a general timing of when we'd get to the expansion cohorts, who will provide more data on the whole program.
Looking at the Dove cohorts et cetera of course, when we feel it's an appropriate time.
But we're making good progress we're encouraged.
Okay also quickly for two patients who received two doses each in Canada, what doses today receipt and Ah how frequent with the dosing.
Well they they initiated on the protocol that that we had in place for cohorts foreign five the same protocol depending on their age.
So that was either to 3.3 dose to start or the five dose the same one.
And so they would receive two one received two and you'll receive four doses I think already.
The poor thing is they've had no no adverse effect at all and more encouraged by how they're doing so.
There's more patient I'm Wanna get treated we're hoping to get the other one is treated.
Great. Thank you very much.
[noise]. Thank you one moment for our next question.
And our next question comes from the line of Joseph Schwartz from SBB Securities. Your question. Please.
Hi, I'm Jerry dialing in for Joe. Thank you for taking our questions. The first one is on Gtx wild too I believe that you previously guided to cohorts six and seven expansion update and late 23 or early twenties late totaled 22 or early 20th 23, but it looks like it will begin enrollment in the first half of 23.
I was just wondering if there are some things that need to be done in order to begin enrollment and for example can be three.
Well, we've already been enrolling cords.
<unk> been already moral so what we said we're completing enrollment those cohorts. In addition of expansion by early in the year. So that's all underway, we just have them.
Not to provide more.
Five point progress and what we said before that we would announce data when we had a substantial amount of data rather than dribbling out bits of data with each cohort.
So we're going to wait until we have a substantial body of data, but we're encouraged by the progress.
Okay got it Uhm and then I have a follow up I guess.
And the press release, you mention that discussions with the F D a to harmonize.
The U S and actually with studies are ongoing I was wondering if you could provide some color on what the F. D. A is looking for in order to make this happen. Thank you very much.
Well, we've previously noted that we would provide some information before it FDA and they wanted a complete set.
Set of data and the terms of a CSR, which we are prepared.
We were working through the process, we usually don't go through the details of the the back and forth for provide the report notification that they requested and we hope we will then be sufficient to reopen the U S study U S site to run the current study so that's ongoing but.
They wanted to just a more complete set and we've been preparing for them.
Thank you one moment for our next question.
And our next question comes from the line of Christopher Raymond from Piper Sandler Your question. Please.
Hey, thanks.
Two questions first on four O one <unk> one.
Just thinking about the European or review process and the Prime designation I know you guys have now just before but.
Just look at it back into the prior data you guys saw corn starch use reduction pretty meaningfully even if we 24 and just kind of curious with the some review.
Is there any chance of an interim look here to serve as the basis for accelerated approval.
Or is that just totally off the table.
And then <unk> I know you guys sort of talked about a protocol amendment can you just clarify is that the reason for the delay.
Finishing enrollment of the phase III.
Just kind of clarify that thanks.
Okay <unk>, we have to serve both U S in Europe , and the trials blinded. So even a six month data were better we had committed to 48 worth of of blinded data for both so was nowhere to use epic sorry, once we get our blinded complete data, though the prime designation will.
Will help us.
The review discussion process to get to a file.
And so that would be the main benefit of but we couldn't use that to shorten the study we'd have to.
We'd have to honor the 48 week blinded main body of the study.
<unk>.
I would say look in general all year because of home across the beginning of the year of sites or an address I think a lot of people who had.
Challenges is getting studies going and we've managed that we're pushing ahead. We are enrolling in the study the placebo, though removal of please just give us the opportunity to see what's going on on each patient we're doing a wide range of ages and we'll be able to see data all along while we're studies going on and more real time allow us to help kind of think through.
The dosing I don't think we're just picking one does it could be dosing algorithm like different ages get different doses, so being able to see the data to fly will just help us get through that and get through faster. So we get the final bit of data in we can make a decision on whether we need to go higher for the younger patients and for what ages. So.
So that's the main benefit to us.
With the data, though will be able of course informed street.
Looks like as well and the younger patients and they will help us also with.
Raising awareness of the Dragon is spelled C. Four people globally and when you look hard at high school Rosset as a strategy and all the data both animal and human it's a very profound effect and a very important way for OIS why we think having the dose data probably will be also helpful to us in and raising awareness and driving our phase III.
[noise]. Thank you. Our next question comes from the line testing Ahmet from Bank of America. Your question. Please.
Hi, good afternoon.
Thanks for taking my question.
Clarification for for U S 14340, I indication can you may be in all set for us expectations on what you would consider to be clinically meaningful data.
And then just reminded about how large you think this population could be for adjusted locations and then secondly to clarify when should we expect to see phase III data for Dts <unk>. Thanks.
Sure so.
Let's start with the size.
For the <unk> or <unk>.
Should be it should address both type one type three anti poor O in that group that.
Which is very.
Raising powerful to be able to do all three types.
That would allow street on the order of 60000 patients.
And developed world So.
Essentially larger than what <unk> <unk>, it's a very meaningful population within the study. The first part of the study the phase two will help us stablish.
The.
The right dose will have biomarker driven data basically to make that decision.
For the phase III with FDA discussion.
The main 301 phase III.
We'll be looking at clinical fractures of regular clinical practice.
Between the treated and placebo group.
We're also going to be running another study at 314 study, which will look at a younger age group with very high fraction, which will randomized.
The truth, Mab or bisphosphonate, which is used in those very severe young patients, which gives us another way to demonstrate the powerful factor, particularly in the young patients were from our own experience and where.
Bone disease, the young patients can really respond to a new drug in a profound way. So we think is another way for us to demonstrate the product.
Study will be open label, but randomize.
So both of us.
That will look at total fractures. So both of them rose new fractures, one clinical fractures. The other total fractures and I think I mean for reduction well this <unk>.
A failed three out of five times studied but the proximate effective maybe about 20% reduction fractures.
We think that this drug will have about a 50% reduction fractures and that's how we power the studies and we think that certainly would be clinically meaningful.
Right now I think that.
There's probably more to these and just fractures and we'll be looking at a number of endpoints, which will help enhance.
The Clinton meaningfulness like how patient feel how they respond because we think those are in their daily lives things those will have impacts on how.
How well the drug will be used and how important it is in there.
Five.
Thank you. Our next question comes from the line of data on her from Stifel. Your question. Please.
Great. Good afternoon. Thanks for taking my questions. One clarification question on the K K C Amendment. So pressed for Mardi does he extension to April 24 also apply to profit share or just cost share and I guess another way transition to royalty base should we expect that to occur starting in April 24 April 23.
<unk>.
And then as a follow up for Gtx one O. Two just wanted to clarify have any patients reach to 14 milligram dose at this point. Thank you very much.
I prefer to jump in very straightforward. So they they are royalty structure takes place at the initial time of transition. So April of 2023 that will have the amendment, we will be able to have additional folks in the field to help to make sure. We have a smooth transition and would continue to grow at Chris.
See that and that will be under the cost sharing arrangement.
With regard to the.
The ancient Gtx wanted to there's one patient III 14, and the titration, but.
There's a large number of patients with many of receive 10 and 12 from the earlier cohort so.
We've moved.
We achieved significant level of drug without having the side effects were encouraged by what we're seeing.
Thank you. Our next question comes from the line Mercury craft from Jeffries. Your question. Please.
Congrats on the update and thanks for taking my questions for.
Four angelman I wanted to see if you can clarify how many new patients who have been dose.
The date of cut off in July for July 12th.
Yeah, I don't think we can give you that precise detail.
I'll try and triangular around we've working through the dose escalation courts, which are can be two to four patients but.
And each one.
We said, we are going to be through them and expect him fully enrolled.
For the end of the year that early first half we would be.
During the expansion cohorts, which is the the larger 20 per group.
Expansion. So that's kind of where we are when will provide any more detailed math moment.
Got it and also for Angelman, there's been some discussion on potential CGI score discordant in the United States versus you in Canada do you have a strategy in place to standardized assessment and reduced bias across sites for the CGI measure.
Yes, certainly that's a question that's fair to be raised I think we were working on an additional training to assure that we're normalizing that I would say also though.
Reliance on the third party like the psychologist assessments is done with the original specific calibrated, scoring system, where you're measuring performance and scoring is a one way to gain the kind of objectivity. We've shown some of that data for example in the Bailey score the violence or with the bally's for particularly because it's psychologist administered not the <unk>.
No parent.
So I would combination of training and also dependents and reliance on some of these independent scores that help give us confidence that what we're seeing is an important effect in and not a placebo effect.
Thank you. Our next question comes from the line of Eagle Natural <unk> from city to your question. Please.
Hi, I'm Ellen team. Thank you very much for taking the questions I had one on the commercial business I think maybe for Marty disregard to the guidance range for <unk> for the fourth quarter. It looks like you need a significant reacceleration in the trajectory to meet the lower end of guidance. So you could just spend a few minutes just clarifying the assumptions around around getting into that.
Guidance range. Thank you.
Okay I'll start by then ARIKAYCE here as well and he can take some commentary on just what's going on with the television we always.
It hasn't been launched for that long that what we've seen with actually both Chris beta and until he is that you do indeed have a heavier fourth quarter as a percentage of the total revenue now.
We expect that were given the health of the business and the growth that we've seen in the start forums and the number of patients treated we expect that again.
Going into the fourth quarter this year for utility and crispy that remind you and Eric I don't know if you want to give any more commentary test on digital V and.
How are we thinking of doing.
Demand is strong and as I have stated it continues to exceed expectations with regards to.
Identifying patients and converting those patients too commercial therapy.
In a timely manner.
The challenge that we're working on is as optimizing the dosing and so we have an educational campaign.
Hey at this time to increase awareness and working closely with both patients and providers.
Around optimal dosing and timing titration of.
Of of the treatment.
And just one quick follow up on the pipeline I thought it was interesting that both for the antibodies to choose them up as well as for the gene therapy in Wilson's disease in a totally unrelated disease you remove the placebo parts of the dose finding I'm just wondering if there's any connection between.
Decisions or if they were just just independent coincident. Thank you.
They are independent <unk> just to be happen to be running for trials at the same time right now so they're all at the same stage.
We always we seek to have the more perfect design, which I think a placebo can be considered a that but sometimes the practical realities of that action inhibits your ability to know what's going on and learn and do things and so we felt like it was going to be better for us to learn what was happening.
Fly and maintain the placebo for the main body of the study, but simplify the upfront part. It also makes it easier to be able to talk to patients about enrolling in the program because they haven't seen the drugs. The doctors didn't know anything about it just helps with that discussion so.
It's totally separate just happens to be where at the same stage, where everything and we're adapting what's the best way forward to get this drug.
Enrolled in.
Advanced as best we can.
Thank you. Our next question comes from the line of June Lee from tourists to your question. Please.
Hi, Thanks for taking our questions you mentioned cost alignment for 2023 can you outline which areas you're focused on any comment on cash slideway.
For one or two is multi domain responder index, a possible way to mitigate lorries given your expertise there. Thank you.
Now suffer with expenses and you can provide a little more detail Sir the main job here is to not spend money plays a don't create value.
<unk> and to really drill harder down on that and our growth we've had a lot of growth.
Manage it maybe already comprise more color on there yeah sure that we've mentioned head count for example, we have had a lot of growth.
For the past couple of years, starting really what the dimension acquisition and so we our goal is to key limit head count and key headcount flat going forward as well as as our operating expenses as well our goal would be to keep opex flat.
Going into 2023, as well and that really and to do that is exactly what ayn Los Ang.
Looking where we can drive value and prioritize and not spend money on things that perhaps would not drive the value that we want in the near term.
And I think that's good housekeeping right. So we've had at this period of growth and.
These are programs that we're implementing and I think we'll see results.
Seeing results. So that's great from a cash runway standpoint, we are in good shape, we have about $1 billion on the on the balance sheet and that takes us.
Yeah, we haven't given specific dates that we always say the next couple of years and definitely through some critical milestone.
Questions, you've asked about one or two and four O one.
So from a cash standpoint, we feel we felt lucky in that we're in good shape, we wanted to take care of that cash moving forward.
Thanks, very so on the on the <unk>.
The multi remain responded to those who are not familiar with that as a way of <unk>.
Essentially a valid many different domains and capturing big wins or big changes.
In a very heterogeneous populations, we think angelman is a prime disease state given the fact that there multiple different domain is five or six demeans of critical importance that you could evaluate reevaluate given and points and you add up the big wins through mentally important difference filter. We think that method allows you to capture efficacy.
Might vary between patients and a population, which would allows it should not have to select the population.
Carefully for the particular thing we're looking at.
So it's one way forward I would say to you that if you're using a bally's or other types of third party measure test you have professional.
Measures, who do the assessments that you can get control as well and you can imagine having a baby receptive and expressive communication store score. For example is the primary endpoint, it's certainly potential.
So we're going to look at all those options and work through the <unk> is not widely accepted by FDA, we did use it in web savvy.
But they are aware of it was that a lot of discussions.
At the senior level there there's a lot of good features to it could be something that would be great for a disease like AIDS or in one of those lots of heterogeneity. So it's in the palette of options right now, but we have time to hit the figure out, but there's so much going on in the interim and that is.
It's not a problem to figure out the end point is really a matter of trying to optimize how we capture efficacy across.
Genius population.
Thank you. Our next question comes from the line you are on orbit from Cowan Your question. Please.
Great. Thanks for taking my question, maybe April just on that point FDA as you know very well is.
Very much a fan of the orca for communication and I believe they even give a grant to validate that endpoint total academic side can you just give us.
And I believe that might have been accepted is of primary importance on <unk>.
Communication.
Is that an toward validation and is there any chance you might explore that or that requires validation a priority.
And that's gonna take too long and then maybe just secondly, once you do selected those would you move to a sort of a placebo phase two before you run the pivotal thank you.
Oh, a familiar we're running the orca and we've seen improvements in the <unk> the.
I think the ORC is near the validation will be done I think it's either done there are going to be done. So I think that's all will happen.
Thing I would say to you is if you when you look at clothes evolve that putting a caregiver assessment as primary is a tricky thing because it can be critiqued.
And as complicated and often there is noise effects loop caregivers assessments in this regard I would generally putting into the salt primary endpoint I think would be a challenge I would much rather see an.
An independent professional valuation score that.
But you Miss something when you're a professional valuate or like the setting is not comfortable in my ultra how patients behave. So we are aware of all that we have time for us to figure it out I think <unk> could variably what are the components of language, whether it would be primary I would I would be less comfortable with it being a primary with.
But the validation will happen it'll be an important part of the overall assessment to help patients due.
The second question was around the phase two would be introduced placebo Oh, yes, that's right.
Well our plan right now does not include running additional space to placebo trial.
Fair question, you're asking are really is how.
How would we know the treatment in fact, we're seeing is sufficiently large should not be placebo. It's been a common discussion item for a lot of people, but I think we're going to be looking for efficacy change that we feel is compelling and repeat and persistent and the kind of thing we think we have seen it.
It gives us confidence that we can get that kind of data if the data.
Less certain than it would raise more questionable whether we have the dose right or not frankly, because I don't think we want to enter phase III unless we have a.
Definitive treatment effect that we're comfortable worth investing in.
If there was a need for that we could consider it but right now we're looking for really solid large rounded efficacy before we head to phase III that would be our preference, but your point well taken but I think that if.
If we can get the kind of efficacy that is incontrovertible in our minds.
Then we moved to phase III.
Thank you. Our next question comes from the line of Salve and Richter from Goldman Sachs. Your question. Please.
Hey, good afternoon, and thanks for taking my questions. This is Elizabeth on for solving for the Wilson data update around the end of next year or early 24 could you provide color on on what signs you're looking for and then on the O. T. C program. If you could discuss how you expect enrollment to progress.
Yeah.
Apparently so for the Wilson update what we expect to have US we're playing will five patients in each of three cohorts.
Now all open label. So we would have 15 patients worth of data you would expect the update include data on the different dose cohort would tell you about urinary copper.
Thrilled plasm and other parameters that relate to comprehend physiology metabolism in Wilson.
Those would be the core measures that would be telling us are we hitting the right dose and what our doses going forward and what the safety looks like in that population. So that's what we did expect to put out at that time.
For OTC, we consciously put OTC after G. S. One startup enrollment running as many trials. We are so we pushed it out a lot of the G. C. One to be our prime focus to get it going in enrolling which it has and will now be adding more effort on OTC to get that rolled it as a 64 week study so is a little bit longer.
It will take more time to enroll will probably have to enroll more outside the U S and in the U S is our expectation, but it's still a 50 patient randomized trial and.
It will take somewhat more time than GSD probably to enroll.
Thank you. Our next question comes from the line of Joe Beatty from our W. Bird Your question. Please.
Thanks for Crispy, though I think you mentioned about about half the new scripts are coming from new prescribers, how does the remaining addressable markets across new prescribers and existing prescribers Mmm second question is on the hemophilia that'd be program returned from bear what could make the transfer to a new partner.
Well, let me answer the second one first and then Eric you can answer the first one so.
So on what came back to those those are hemophiliac a program.
They had acquired significant data at a number of patients who had.
Great reduction in events.
And they decided it wasn't meeting with quite care. They wanted they had other priorities and.
So they decided to bring it back to us.
What we're looking for US first of all we have a lot of our players. The company, we don't want to put more money into an area, where we're not experts. So we think hemophilia still has room with environments program getting there, but I think there's still room for a better gene therapy, we do think that the type of avian our manufacturing large scale may.
Faction process would be.
I think a benefit.
And we are looking for a partner wants to pick up development and we'd be happy to do the manufacturing we have a new plant.
As well, which would give us an edge.
And we'd be looking to use our pinnacle PCL platform, then to manufacturer that product.
We think that they are still a lot of room left for something better Eric Once you answer the question on.
Prescribers. So if if you think about the current market penetration.
For pediatric patients is about 40% in adult patients is about 15%.
We continue to believe that the majority of the pediatric patients will get treated and.
About 50, 50% half of the adult patients, we'll eventually end up on treatment.
As we've been stating.
Many of these patients that we're finding these days if not most of these patients are in the community setting.
With doctors that.
Are not necessarily associated with the traditional metabolic bone center. So it takes time to find those patients and get them refer to someone that's gonna.
That will you to treat them.
Or initiated treatment.
Four new prescribers.
Thank you all right.
Our next question comes from the next question. Thanks, Lisa Baker from Evercore ISI.
Hi, there how you doing.
Hi, there.
I just wanted to ask a couple of questions on Wilson's disease, I think just amended the child design and you'll be able to evaluate a couple of preliminary doses.
Can you talk about any potential signals are you looking for in that data to evaluate if there's any advocacy like what what should we be looking for in this initial date et cetera, and what would their opinion patriot efficacy.
Well first of all the all the patient of the trial would have been unstable key later therapy for awhile. So they already have sort of dream their copper.
We're going to be looking at urinate copper and then yearning copper after you remove their drugs at some point, but the first part rolling it whether we're reducing the amount of carpet ends up in the urine with their key later versus not.
We'll also be looking at.
Copper loaded ceruloplasmin or through plasma activity.
That will tell us how much copper is getting loaded through plug which is very low in Wilson is one of the unique features of.
Gene therapy is that we can restore normal copper distribution, which you can't do with a key later so we think that's a really important feature and we showed in the animal model that we could get to.
Significant increases in through replies loading and delivery. So that's an easy measure from the bloodstream.
Find that with urine copper serum copper.
And probably a few other biochemical measures.
Would be.
That will be the basic way, we'll make the decision on dosing.
It would be <unk> copper various types as well as through Plasm I think is at the core of it of course is safety.
Transaminase and safety and how patients are doing overall, but I think most of it's gonna be driven off copper biochemistry.
And would that be kind of the the the regulatory endpoint as well or.
Is that maybe you could just give us a little background I understand that's a critical to this day. He's just curious on.
How relevant it is for the bigger picture.
Yeah, so the regulatory discussion focused on urinary copper.
Some people have been using plasma are free copper the agency actually preferred urinary copper and so that is accepted primary endpoint look at your in corporate control.
And we'll do it while they're on their drive, but also to take them off their drugs.
And control to show that we can.
Keep urinary copper low.
Wow load it well, they're getting less.
They won't have any copper chelation going on so that makes sense. So we'll be able to show get rid of their old treatment needs, a new treatment and still maintain low urinary copper.
So that is the agreed upon evaluation.
It's one advantage of the Wilson program is that there was clear bias marker type and points that are meaningful that the F. D. A has already accepted because of the use of key leaders in there prior approval.
Thank you and our final question for today is a follow up from the line of vehicles not to move it from city. Your question. Please.
Hi, Thanks, very much for taking the follow up I just wanted to follow up on your own question around the placebo for an Angel men's phase two or phase III.
Because you know in the in the prior over trial the placebo effect was around eight.
That was a mixture of deletion mutation patients as you know I'm, assuming that if you do a phase two or phase III that you'll only enrolled the deletion place patient and based on some of our analysis of the literature and Angelman would suggest a placebo effect substantially below 0.8, just wondering what your thoughts are on that and if you could confirm that you do a pivotal trial and error.
Women's that it would be 100 per cent deletion patients. Thank you.
Yes, there are pivotal plans to do all deletion, because you think including a variation of tie it will create a lot of areas not only around the CGI score, but also around all the other scores. So the last thing you want is already a lot of heterogeneity you on more heterogeneity. So the phase III will be strictly the deletion type, which is 70% of the population.
And we will conduct some other companion studies that would help expand and understand the use of the drug in the other types like <unk> parental diathermy or the <unk> type of patients. So.
So we will want to cover the whole thing for the label with the random I said it will focus on the severe population.
If we can prove in a placebo trial that we've treating severe population the other stories will be easy.
To reach consensus.
I think controlling noise is extremely important in these type of designs and so by mixing types.
Even though it might even if regulars wanted I would resist it because it could harm your outcomes and create a more effect. If you look at natural history and the severe patients. They are very flat. They do not change who do not gain ground unexpressive receptive communication significant ground. So we think by not mixing with some patient.
Who do gain some ground unexpressed receptive you will.
Avoid that noise. So it is part of our strategy just to keep it tight.
And therefore be more confident about this FX we're seeing.
<unk>. This does conclude the question and answer session of today's program I would like to hand, the program back to Joshua He got for any further remarks.
Thank you. This concludes today's call there any additional questions. Please.
And ultra <unk> Dot com, thank you for joining us.
Thank you, ladies and gentlemen, which your participation in today's conference. This does conclude the program you may now disconnect good day.
The conference will begin shortly to raise your hand during Q&A you can dial 911.
[music].
[music].
[music].
[music].