Q2 2022 Ultragenyx Pharmaceutical Inc Earnings Call

July 28, 2022

The conference will begin shortly to raise your hand during Q&A you can dial star one one.

[music].

The conference will begin shortly.

Good afternoon and welcome to the Ultragenyx second quarter financial results conference call.

Good afternoon, and welcome to the Altra genetics second quarter financial results Conference call. At this time, all participants are in a listen only mode.

At the end of the prepared remarks, you will have the opportunity to ask a question during the Q&A portion of the call. It is now my pleasure to turn today's call over to Joshua Hager Executive director and head of Investor Relations.

Thank you.

We issued a press release detailing our financial results, which you can find on our website at <unk> Dot com.

Joining me on this call our ammo CAC as Chief Executive Officer, and President, Eric Harris, Chief Commercial Officer, Mardi Dier, Chief Financial Officer, Camille Bedrosian, Chief Medical Officer.

To raise your hand during Q&A, you can dial star 1 1.

At this time, all participants are on a listen-only mode.

I'd like to remind everyone that during today's call, we will 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 I will now turn the call over to Amy.

Good afternoon, and welcome to the Ultragenyx second quarter financial results conference call.

At the end of the prepared remarks, you will have the opportunity to ask a question during the Q&A portion of the call.

It is now my pleasure to turn today's call over to Joshua Higa, Executive Director and Head of Investor Relations.

Thanks, Josh and good afternoon, everyone.

We're now six months into the year and across the company will continue to make meaningful progress against our goals.

The team delivered another solid quarter of revenue growth as they commercialize their products across the globe.

We acquired the late stage product <unk> 111 from MTF Threet for NPS, three eight or sanfilippo syndrome in an MTF is easier for which we have extensive experience.

In July we bolster our cash position with a substantial royalty financing that also enabled us to acquire genetics and gain full control of our important Angelman program.

These activities along with progress across all of our early and late stage clinical programs put us in good strong position over the coming years for exceptional value creation.

I want to touch on a couple of pipeline update before turning the call over to the other leadership team members to provide more detail on the quarter.

At this time, all participants are on listen-only mode.

I'd like to remind everyone that during today's call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially.

At the end of the prepared remarks, you will have the opportunity to ask a question during the Q&A portion of the call.

Please refer to the risk factors discussed in our latest SEC filings.

Starting with Gtx 102 for Angelman syndrome.

A seminal moment in this program with the acquisition of genetics.

And now have full control over the Gtx 102 program.

As we said on our call last week, we are all in on Angelman syndrome.

With the exceptional science regarding the target region and with the excellent data we've seen to date in phase one two study.

I'll now turn the call over to Emil.

It's rare to see a significant improvement and development function as we have seen recently.

This is something I haven't seen.

30 years of drug development.

Thanks, Josh, and good afternoon, everyone.

We're now six months into the year, and across the company, we continue to make meaningful progress against our goals.

Last week, we shared data that demonstrate our ability to safely dose patients with gtx, one to add up to 10 milligram doses.

The commercial team delivered another solid quarter of revenue growth as they commercialized our products across the globe.

We observed meaningful critical changes in a group of children that are severely impacted by the disease due to the deletion of them return on <unk> three gene region.

We acquired the late-stage product UX111 from MPS3A, or Sanfilippo Syndrome, an MPS disease area for which we have extensive experience.

This severe mutation always predicts a very slow rate of learning on natural history as Dr. Byrd Kravitz, one of the principal investigators on the study said on our call last week.

These early clinical responses across multiple domains and multiple clinical measures have been independently confirmed by clinician therapist and patient families.

It is now my pleasure to turn today's call over to Joshua Higa, Executive Director and Head of Investor Relations.

We observed statistically significant improvements for some of these children and expect to further enhance the in effect by increasing loading doses and providing more time in the study.

One specific measure I would like to highlight is the bayley scales into development Bailey I'd like to remind you. The bally's austerity measure used to diagnose if I'm a little delay in childhood.

Please refer to the risk factors discussed in our latest SEC filings.

I'll now turn the call over to Emil.

<unk> is administered in the clinic by trained therapists not the investigator and.

In Belize, often used in clinical trials to assess cognitive language and motor development in children.

Thanks, Josh, and good afternoon, everyone.

We're now six months into the year, and across the company, we continue to make meaningful progress against our goals.

In this study we're using the latest version of Bally, which allows for evaluation of children with delays exceed the bally age limit of neuro typical children.

The commercial team delivered another solid quarter of revenue growth as they commercialize their products across the globe.

Starting with GTX-102 for Angelman Syndrome, we reached a seminal moment in this program with the acquisition of genetics and now have full control over the GTX-102 program.

The extensive historical data with this measure it allows the ability to assess statistical significance threshold for improvement when evaluating individual patient results and showing their different from.

Air or variation, we know from natural history, and the scores that measure do not meaningfully change for patients with Angelman syndrome, particularly those with deletion type mutation.

As we said on our call last week, we are all in on Angelman Syndrome with the exceptional science regarding the target region and with the excellent data we've seen to date in Phase I-II study.

Receptive and expressive communications hub scores that are important part of daily, particularly for patients with Angelman syndrome lack communication skills.

It's rare to see a significant improvement in development function as we have seen recently.

This is something I haven't seen in 30 years of drug development.

Cross the patient in cohort four and five and treated for a minimum of 128 days.

Last week, we shared data that demonstrated our ability to safely dose patients with GTX-102 at up to 10 milligram doses. We observed meaningful clinical changes in a group of children that are severely impacted by the disease due to the deletion of the maternal UB3A gene region.

This severe mutation always predicts a very slow rate of learning on natural history, as Dr. Barry Kravitz, one of the principal investigators on the study, said on our call last week.

These early clinical responses across multiple domains and multiple clinical measures have been independently confirmed by clinicians, therapists, and patient families.

We observe significant improvements for some of these children and expect to further enhance these effects by increasing loading doses and providing more time in the study. One specific measure I would like to highlight is the Bayley Scales Infant Development, or Bayley.

I'd like to remind you that Bayley is a standardized measure used to diagnose developmental delay in childhood. It is administered in the clinic by a trained therapist, not the investigator, and Bayley is often used in clinical trials to assess cognitive, language, and motor development in children. In this study, we're using the latest version of Bayley, which allows for evaluation of children with delays who exceed the Bayley age limit of neurotypical children.

709 children showed a statistically significant improvement in either Bally receptive.

The extensive historical data with this measure allows the ability to set statistics and infant thresholds for improvement when evaluating individual patient results and showing they're different from error or variation.

Operator, it seems like we might have lost <unk> audio connection can you confirm if are still out there.

One moment.

<unk> is still connected.

I am here, Josh Okay loud and clear go ahead, and we'll continue alright.

We know from natural history that scores in this measure do not meaningfully change for patients with Angeman syndrome, particularly those with deletion-type mutations. Receptive and expressive communication subscores are an important part of Bayley, particularly for patients with Angeman syndrome who lack communication skills.

Receptive prep communications important part of the daily, particularly for patients with Angelman syndrome, who lack communication skills.

Across the patients in Cohort 4 and 5 who were treated for a minimum of 128 days, 7 of 9 children showed a statistic in infant improvement in either Bayley receptive...

Across the patients in cohort four and five and treated for a minimum of 128 days seven of nine children.

Sure a statistically significant improvement in either bally receptive or expressive communication score as of their most recent evaluation.

This compares favorably to two three of the original five patients who were treated in the US who have statistically significant changes in the same score at day 128.

Our results from the original five patients also included patient reported results that were well past. The day 120 time point since many patients. We're four months pass their last dose at the time of that data release.

So the graph resulted this objective third party measure combined with the Bally signings from natural history studies give us confidence that we are improving communication skills and angelman syndrome in a meaningful manner.

The full potential of improvement to Bally communication measures will likely depend on the following patients for a longer period of time and starting with higher doses.

In fact, all three of the ex U S patient to reach the day 170 evaluation in the current steady improved in bulk receptive and expressive communication beyond their day 128 results before receiving their first maintenance dose.

We have also amended the protocol in the UK and Canada and have begun dosing patients in additional dose selection cohort with two patients dosed at the higher 755 dosing starting doses for the loading phase that we've already used to treat patients in cohort four and five.

One other important step forward the first patients from the originally treated US cohorts was readout last week in Canada with no reported drug related safety event.

Our team is also working to found in our clinical study report with the FDA to support discussions that would allow for a harmonization of the U S and ex U S protocols.

With all of these components come together. This is the right point, but I'll check the lead development of this program.

We have the right expertise and capability to ensure a robust clinical program and regulatory strategy for <unk> 102.

The history of development of Gtx, one two the inspiring story for our team.

Storage group of parents, who defied the odds and their relentless pursuit of the right science and search for the right partner.

I firmly believe the right sized was discovered and Scott into the lab and we now have an opportunity to bring one of the first Eric treatments to the <unk> community.

In the second quarter, we also announced its agreement to take on U S 111 in AAV gene therapy for the treatment of <unk> or sanfilippo syndrome.

<unk> disease and gene therapy are very familiar territory for us.

And we believe that we can make a meaningful difference whether the sample label community.

In the past we work closely with the FDA to establish the use of alternative trial defined endpoint to achieve approval and we believe the <unk> hundred 11 data are strong and support the use of the <unk> approval pathway.

Our team is hard at work on the filing strategy for a discussion with the agency and we look forward to providing updates later in the year.

With that I'll turn it turn it over to the team to provide updates on their function.

Operator?

Thank you Emma and good afternoon, everyone I'll start by section discussing our team's continued success commercializing Chris meter before shifting to the.

It seems like we might have lost Emil's audio connection.

<unk> for.

Chris leader within the profit share territory, we continue to find adult new adult and pediatric patients more than four years since launching the product.

The end of the second quarter over 2600 patients have been prescribed Chris leader and more than half are adults.

In the U S. We have penetrated almost 40% of the pediatric market and approximately 15% of the adult market <unk>.

Recall, finding pediatric patients similar to many other rare diseases, where the treatment is consolidated into centers of excellence.

This contrasts to the finding.

Adult patients, who are who are mostly being treated by community based physicians scattered across the country.

Our team is leveraging a mix of traditional in person meetings, along with innovative and interactive virtual programs to educate health care providers and patients as well as enhancing our digital online education presence.

We also recently launched education initiatives to specifically target nurses and physicians assistance that often work with caregivers and the entire family to develop a comprehensive treatment plans for patients.

We believe there is meaningful opportunity to steadily grow. The proceed of franchise with new identify patients as well as continued strong adherence within existing patients even four plus years into launch.

We will continue our efforts as we look towards transitioning the commercial responsibilities outside of the medical geneticist to key our Karen in April 2023.

Outside of the profit share territory, primarily in Latin America. We are now seeing the results of our early launch efforts.

In the second quarter revenue grew 32% versus the first quarter 2022.

And then the first half of the year, we have already surpassed the total revenue generated in this region last year and.

In Latin America. There are there are over 250 patients on reimbursed therapy.

This will continue to grow as we continue expanding in Brazil, and as we gain momentum from our recent launches in Colombia and Mexico.

In Argentina, we continue to support named patient requests and look forward to gaining regulatory approval over the coming quarters.

Across all of the ultra <unk> regions, Chris Frito revenue in the first half of 2022 grew 37% compared to the first half of 2021.

Based on our performance to date, we are reaffirming our 2022 revenue guidance and ultra genex territories of $250 million to $260 million.

Turning now to the JV and beginning with our efforts in the U S. We continue to see steady growth across all of the leading indicators as a result of broad use in key metabolic genetic clinics across the U S.

One of the more promising statistics is that approximately 90% of all cases are approved for reimbursement in less than 30 days.

This isn't even faster turnaround time than we saw for our press feeder at a similar stage of commercialization.

The team is also moving beyond the major centers for inborn errors of metabolism and is expanding the call coverage to other high potential health care professionals.

They are leveraging machine learning and artificial intelligence to generate new leads similar to what we are doing for Christina.

Outside of the U S use of <unk> continues to add new physicians and patients through our named patient.

Early access programs in Europe .

In France, and Italy, there continues to be meaningful demand through our named patient program and we are starting to respond to requests for named patient programs across other countries in Europe .

In Brazil, the health authorities approved the <unk> for the treatment of both pediatric and adult patients with LC <unk>.

Late last year.

We're continuing to work through the process to get full reimbursement approval, but this can take a little bit of time to complete.

At this point in the year, we are reaffirming the guidance of $55 million to $65 million that we put out in January .

I look forward to providing another update on this and other commercial programs next quarter.

Can you confirm if we're still out there?

With that I'll turn the call over to Marty to share more details on the financial results for the quarter. Thanks.

One moment.

Thanks, Eric.

Earlier today, we issued a press release that included financial results for the quarter, which I will briefly summarize.

I do show him still connected.

Company revenue for the three months ended June 32022 totaled $89 3 million.

I'm here.

Christy the revenue in <unk> territories for $64 million, including $51 6 million from the North American profit share territory, and net product sales of $12 4 million in other regions.

Total royalty revenue related to the sales of Christina and the European territory with $5 4 billion.

The agility revenue for the second quarter 2022, with $13 5 million.

<unk> revenue for the same period last $4 9 million.

Our total operating expenses for the second quarter 2020.

$230 9 million, which includes research and development expenses of $1 54, 5%.

SG&A expenses of 68.1 and cost of sales of $8 3 million.

For the second quarter ended June 32022, net loss was $158 2 million or $2 26.

Sure.

During the first half of the year there've been a number of noncash items that have impacted net loss.

This includes approximately $65 million of stock based compensation $20 million related to the decline in fair value of our equity investments and $13 million of noncash interest expense related to the royalty pharma transaction.

Is there offset by approximately $10 million of noncash revenue also related to the royalty.

We ended the quarter with approximately seven $706 million in cash cash equivalents in marketable securities.

In July, we bolstered our cash position with a substantial royalty financing that also enabled us to acquire genetics and gain full control of our important Angelman program. These activities, along with progress across all of our early and late-stage clinical programs, put us in good, strong position over the coming years for exceptional value creation.

<unk> ended the quarter in July we raised $500 million in non equity dilutive capital and then non dilutive non equity dilutive capital transaction with <unk> capital markets for the sale of a portion of our North America, Chris Bate a royalty.

I want to touch on a couple of the pipeline updates before turning the call over to the other leadership team members to provide more detail on the quarter. Starting with GTX102 for Angelman Syndrome, we reached a seminal moment in this program with the acquisition of genetics and now have full control over the GTX102 program.

Also exercised our option to acquire genetics and paid $75 million in July which allows us to take over the development of Gtx 102.

As we said on our call last week, we are all in on Angelman Syndrome, with the exceptional science regarding the target region and with the excellent data we've seen to date in Phase I-II study.

We are well capitalized with over $1 billion in the bank and we are making operating decisions to stage spend on our development programs and slowing head count growth in order to manage our burn.

It's rare to see a significant improvement in development function as we have seen recently.

As we have said 2022 with a peak burn year for us as we have initiated multiple late stage clinical programs.

And licensed at Chiesa completed the acquisition of genetics and are completing the build out of our gene therapy manufacturing facility.

In 2023, we don't anticipate additional one time events at this nature or large capital capital expenditures and we anticipate SG&A will decrease compared to 2022, as we transition U S and Canadian commercialization responsibilities for Kristina to Kate Casey.

We'll continue to invest in our clinical and preclinical programs as discussed and the overall net effect across the company then will be a decrease in net cash burn.

Josh?

Now I'll turn the call over to Camille.

Okay.

Thank you Marty and I too wish everyone. Good afternoon.

Loud and clear.

This is something I haven't seen in 30 years of drug development.

This is truly an exciting time for clinical development at Alto <unk> we.

Go ahead, Emil.

Last week, we shared data that demonstrated our ability to safely dose patients with GTX102 at up to 10 milligram doses. We observed meaningful clinical changes in a group of children that are severely impacted by the disease due to the deletion of the maternal UB3A gene region.

We have seven programs in the clinic, including our ASO for Angelman syndrome that <unk> discussed earlier.

On mrna for glycogen storage disease type three.

For late stage gene therapy trials, and the phase two three monoclonal antibody for osteoporosis and protector.

Continue.

And my section on today's call I will focus on this antibody UX 143 or <unk>.

We are developing for osteogenesis imperfecta.

All right.

This severe mutation always predicts a very slow rate of learning on natural history, as Dr. Barry Kravitz, one of the principal investigators on the study, said on our call last week.

Osteogenesis imperfecta Oi is caused by a defect in collagen that results in significant bone weakness and bone fragility, leading to factors deformities.

Receptive and expressive communication is an important part of Bayley, particularly for patients with Angeman syndrome who lack communication skills.

Across the patients in Cohort 4 and 5 who were treated for a minimum of 128 days, 7 of 9 children showed a statistic in infant improvement in either Bayley receptive or expressive communication score as of their most recent evaluation.

And pain.

This compares favorably to three of the original five patients who were treated in the U.S. who had statistically significant changes in the same score at day 128.

These early clinical responses across multiple domains and multiple clinical measures have been independently confirmed by clinicians, therapists, and patient families.

Currently there are no approved therapies for Oi.

Our results from the original five patients also included patient report results that were well past the day 128 time point since many patients were four months past their last dose at the time of that data release.

We observed significant improvements for some of these children and expect to further enhance these effects by increasing loading doses and providing more time in the study.

One specific measure I would like to highlight is the Bayley Scales Infant Velmar Bayley.

As a company we have spent a lot of time studying bone biology with X L. H Tio and our preclinical candidate for Oi before we did the deal for <unk>.

I'd like to remind you that Bayley is a standardized measure used to diagnose vulnerable delay in childhood.

It is administered in the clinic by trained therapists, not the investigators.

So the results of this objective third-party measure combined with the Bayley findings from natural history studies give us confidence that we are improving communication skills in Angeman syndrome in a meaningful manner.

Bayley is often used in clinical trials to assess cognitive, language, and motor development, in children. In this study, we're using the latest version of Bayley, which allows for evaluation of, children with delays who exceed the Bayley age limit of neurotypical children.

One of our key insights is that <unk> is not simply an issue of collagen is excessive bone resorption and the inadequate production of new bone triggered by this abnormal collagen that leads to low bone mass.

The full potential of improvements in Bayley communication measures will likely depend on the following patients for a longer period of time and starting with higher doses. In fact, all three of the ex-U.S. patients to reach the day 170 evaluation in the current study improved in both receptive and expressive communication beyond their day 128 results before receiving their first maintenance dose.

The extensive historical data with this measure allows the ability to set statistics and infant, thresholds for improvement when evaluating individual patient results and showing they are different from error or variation.

We know from natural history that scores in this measure do not meaningfully change, for patients with Angevin syndrome, particularly those with deletion-type mutations.

Receptive and expressive communication subscores are an important part of Bayley, particularly, for patients with Angevin syndrome who lack communication skills.

Across the patients in cohort 4 and 5 who were treated for a minimum of 128 days, seven, of nine children showed a statistical improvement in either Bayley receptive or receptive thresholds.

What we have found is that if you increase bone formation and reverse the access of bone resorption, you can improve brand strength, even with the abnormal collagen.

And improved fracture prevention.

We believe this insight gives us the opportunity to change the future for patients with osteogenesis imperfecta.

We have also amended the protocol in the UK and Canada and have begun dosing patients, in the Additional Dose Selection Cohort with two patients dosed at the higher 7.5 and 5 mg dosing for the loading phase that we have already used to treat patients in Cohort 4 and 5.

I won't take time today to go back to all the details of the phase two the asteroid data that Mario has already presented.

One other important step forward, the first patient from the originally treated US Cohort, was re-dosed last week in Canada with no reported drug-related safety events.

I do want to remind you of a few of the most important points.

Our team is also now working to file an interim clinical study report with the FDA to support, discussions that would allow for a harmonization of the US and ex-US protocols.

This trial was a large randomized blinded study of 90 adult patients with <unk> being studied across three different dose levels.

After 12 months the results indicated dose dependent and statistically significant effect on bone formation and bone mineral density.

Furthermore, the substantial bone mineral density improvement occurred across multiple.

Anatomical sites and the observed substantial bone formation, we believe is a very important factor in improving bone strength.

All of these findings were accompanied by a favorable safety profile.

With all these components coming together, this is the right point for Ultragenyx to, lead development of this program. We have the right expertise and capability to ensure a robust clinical program and regulatory, strategy for GTX-102.

Similar to how we develop grossing app for XL age when we took over development from care with Karen we are taking these impressive status and that results in adults with Hawaii and looking to further improve upon them for pediatric patients.

The history of development of GTX-102 is an inspiring story for our team.

Currently we are enrolling and dosing patients with Oi between the ages of five in 25 years with.

It's a story of a group of parents who defied the odds in their relentless pursuit of the, right science in search for the right partner.

I firmly believe the right science was discovered in Scott Dindo's lab, and we now have an opportunity, to bring one of the first-ever treatments to the Angelin community.

In the second quarter, we also announced an exclusive agreement to take on UX111 and AAV, gene therapy for the treatment of MPS3A or Sanfilippo syndrome.

With the goal of using the CRM bone formation marker.

One N P to optimize the dose.

Once we have determined the pediatric dose strategy.

We will transition directly into phase III evaluating the benefit institution add on factor.

With this update I will now turn back the call to Emil Thank you.

Operator, it seems like we might have lost Emil's audio connection.

And when we're having a little bit of a hard time I'm happy to finish this out.

I am fine I, just the problem with my phone, but im buying now thank you.

MPS disease and gene therapies are familiar territory for us, and we believe that we can, make a meaningful difference for the Sanfilippo community.

Can you confirm if we're still out there?

So thank you may outgrow shifts in the Q&A portion of the call I'll provide a quick reminder, key upcoming milestones.

One moment.

I do show him still connected.

I'm here.

For you it's $1 three an osteogenesis imperfecta will continue enrolling patients in the phase II portion of the study and expect to provide an update on the dose strategy for the phase III portion of around the end of the year.

Josh?

Okay.

Loud and clear.

We expect to initiate a study in children under five years old in the second half of the year.

In the past, we've worked closely with the FDA to establish the use of alternative trial, designs and endpoints to achieve approval, and we believe the UX111 data are strong and support the use of the accelerated approval pathway.

Go ahead, Emil.

And our gene therapy pipeline with <unk> 111 for Sanfilippo, we are continuing to fall of patients have been dosed.

Continue.

The pivotal study are continuing to evaluate the feasibility of filing for approval based on convincing biomarker data.

All right.

So, Bayley is an important part of Bayley, particularly for patients with Angevin syndrome, who lack communication skills.

Across the patients in cohort 4 and 5 who were treated for a minimum of 128 days, seven, of nine children showed a statistical improvement in either Bayley receptive or expressive communication score as of their most recent evaluation.

This compares favorably to three of the original five patients who were treated in the U.S, who had statistically significant changes in the same score at day 128.

Our results from the original five patients also included patient-reported results that, were well past the day 128 time point, since many patients were four months past their last dose at the time of that data release.

We will continue enrolling the phase III for <unk> 401, and first stage of the <unk> 701 study.

Our team is hard at work on the filing strategy for our discussion with the agency, and we, look forward to providing updates later in the year.

We also expect to finalize startup activities for T. J 301, and begin dosing patients later this year.

With that, I'll turn it over to the team to provide updates on their functions.

Thank you, Emil, and good afternoon, everyone.

On the manufacturing side, we will continue to build out of our facility in Bedford, Massachusetts, which is on track to begin producing material in the first half of 2023.

I'll start my section discussing our team's continued success commercializing Crisvita, before shifting to Djovi. For Crisvita, within the ProfitShare territory, we continue to find new adult and pediatric, patients more than four years since launching the product. As of the end of the second quarter, over 2,600 patients have been prescribed Crisvita, and more than half are adults.

In the U.S., we have penetrated almost 40% of the pediatric market and approximately, 15% of the adult market. Recall, finding pediatric patients is similar to many other rare diseases where the treatment, is consolidated into centers of excellence.

This contrasts to the finding adult patients who are mostly being treated by community-based, physicians scattered across the country.

For <unk> three in glycogen storage disease type III in the second half of the year, we expect to share single dose data from the first part of the phase one two study.

Our team is leveraging a mix of traditional in-person meetings, along with innovative, and interactive virtual programs to educate healthcare providers and patients, as well as enhancing our digital online education presence.

We also recently launched education initiatives to specifically target nurses and physicians, assisted.

, and David B.

And to initiate the repeat dosing stage.

At this point in the year, we are reaffirming the guidance of $55 to $65 million that we put out in January.

So, the results of this objective third-party measure, combined with the Bayley findings, from natural history studies, give us confidence that we are improving communication skills in Angevin syndrome in a meaningful manner.

For Gtx 102 in Angelman syndrome, where also continue enroll cohorts six and seven at seven five or 10 milligrams outside the U S. Our expectation is to provide the next update once we have determined on optimal dosing of gathered substantial data from the expansion cohort.

The full potential of improvements in Bayley communication measures will likely depend, on the following patients for a longer period of time and starting with higher doses. In fact, all three of the ex-U.S. patients to reach the day 170 evaluation in the current, study improved in both receptive and expressive communication beyond their day 128 results before receiving their first maintenance dose.

We've also meant that the protocol in the U.K. and Canada have begun dosing patients, in the additional dose selection cohorts with two patients dosed at the higher 7.5 and 5 mg starting doses for the loading phase that we've already used to treat patients in Cohort, 4 and 5.

One other important step forward, the first patient from the originally treated U.S. cohort, was re-dosed last week in Canada with no reported drug-related safety events.

Our team is also now working to file an interim clinical study report with the FDA to support, discussions that would allow for a harmonization of the U.S. and ex-U.S. protocols.

All of these programs create a distinct opportunity to make meaningful difference for patients that are the reason we believe we have one of the most robust diverse late stage pipelines in rare diseases.

With all of these components coming together, this is the right point for Ultragenyx to lead, development of this program. We have the right expertise and capabilities to ensure a robust clinical program and regulatory strategy for GTX-102.

The history of development of GTX-102 is an inspiring story for our team.

It's the story, of a group of parents who defied the odds in their relentless pursuit of the right science in search of the right partner.

With that let's move on to your questions. Operator, please provide the Q&A instructions.

I firmly believe the right science was discovered in Scott Dindo's lab, and we now have an opportunity to bring one of the first-ever treatments, to the Ange1 community.

Thank you, ladies and gentlemen, I would like to ask a question. Please press star one one when your touch tone telephone again, if you would like to ask a question. Please press star one one.

I look forward to providing another update on this and other commercial programs next quarter.

In the second quarter, we also announced an exclusive agreement to take on UX111 and AAV gene therapy for the treatment of MPS3A or Sanfilippo syndrome.

MPS disease and gene therapies are familiar territory for us, and we believe that we can, make a meaningful difference for the Sanfilippo community.

In the past, we've worked closely with the FDA to establish the use of alternative trial designs and endpoints to achieve approval.

With that, I'll turn the call over to Marty to share more details on the financial results for the quarter.

We believe the UX111 data are strong and support the use of the accelerated approval pathway.

One moment please.

Our team is hard at work on the filing strategy for our discussion with the agency, and we, look forward to providing updates later in the year.

Thanks, Eric.

With that, I'll turn it over to the team to provide updates on their functions.

Our first question comes from Gena Wang of Barclays. Your line is open.

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 June 30, 2022 totaled $89.3 million. CRISPVIDA revenue in Ultragenyx territories was $64 million, including $51.6 million from the North America Profit Share Territory and net product sales of $12.4 million in other regions.

Thank you, Emil, and good afternoon, everyone.

Total royalty revenue related to the sales of CRISPVIDA in the European territory was $5.4 million.

De Jovi revenue for the second quarter, 2022, was $13.5 million.

NEPSEVI revenue for the same period was $4.9 million. Our total operating expenses for the second quarter, 2022, were $230.9 million, which includes research and development expenses of $154.5 million, SG&A expenses of $68.1 million, and cost of sales of $8.3 million.

For the second quarter ended June 30, 2022, net loss was $158.2 million, or $226 per share. During the first half of the year, there have been a number of non-cash items that have impacted net loss. This includes approximately $65 million of stock-based compensation, $20 million related to the decline in fair value of our equity investments, and $13 million of non-cash interest expense related to the Royalty Pharma transaction. These are offset by approximately $10 million of non-cash revenue, also related to the EU royalty.

We also exercised our option to acquire genetics and paid $75 million in July, which allows us to take over the development of GETX 102.

I'll start my section discussing our team's, continued success commercializing Crisvita before shifting to Djovi. For Crisvita, within the ProfitShare territory, we continue to find new adult and pediatric patients more than four years since launching the product. As of the end of the second quarter, over 2,600 patients have been prescribed Crisvita, and more than half are adults.

I have two quick questions first one is a Chris <unk> just wanted to make sure I heard correctly that you penetrate 15% adult market.

We ended the quarter with approximately $706 million in cash, cash equivalents, and marketable securities. Subsequent to the end of the quarter, in July, we raised $500 million in non-equity dilutive capital in a non-equity dilutive capital transaction, with Omer's Capital Markets for the sale of a portion of our North America Crisp Vita Royalty.

In the U.S., we have penetrated almost 40 percent of the pediatric market and approximately 15 percent of the adult market. Recall, finding pediatric patients is similar to many other rare diseases where the treatment is consolidated into centers of excellence.

If that's the case I'm wondering how would you expand market.

Sure.

How active you are to leverage family tree and the second question is regarding the Engelman program. Thank you.

Early this week update or wanted to note that the.

Expansion cohort would that still be definition to clinical benefit will be to score in two domains and are you willing to open to dose higher than 14 milligram.

Okay. Let me ask the second one first and then Eric you did touch on this cruise speed adult peds penetration question.

So on the expansion.

We are still using the two plus do you mean to create share for titration and we expect that we're going to be very close to where we need to be in fact.

We're going to be looking at all of our efficacy results, including the longer term results often tell us a little bit more about where we're at but we're that's what we expect.

We don't expect to have to go beyond 14, frankly, I think we're very close so right now I wouldnt speculate on that I don't think I don't think it can be necessary. Once we start loading. It. This next cohort level, but we will.

Want to make sure we do get the dose right and so we'll continue to evaluate what we're seeing both in the CGI score, but also on the quantitative scores and also over longer periods of time to make sure. We're getting to a dose level that will provide us a substantial meaningful clinical benefit that we could study in phase III.

This contrasts to the finding of adult patients who are mostly being treated by community-based physicians scattered across the country.

Our team is leveraging a mix of traditional in-person meetings along with innovative and interactive virtual programs to educate healthcare providers and patients, as well as enhancing our digital online education presence.

Now for the penetration I think we've been talking about the challenges of.

We also recently launched education initiatives to specifically target nurses and physician's assistants that often work with caregivers and the entire family to develop a comprehensive treatment plan for patients.

Finding adults were proceeded but the good part of them, we find them when they do get prescribed.

We believe there is meaningful opportunity to steadily grow the Crisvita franchise with, new identified patients, as well as continued strong adherence within existing patients even four-plus years into launch.

Yeah.

We will continue our efforts as we look towards transitioning the commercial responsibilities outside of the medical geneticists to Kiawa Kirin in April 2023.

So Eric maybe you can touch on the issue she's asking about with regard to penetration of the adult market, 15% versus piece, where it's much higher.

Outside of the Profiteer Territory, primarily in Latin America, we are now seeing, the results of our early launch efforts. In the second quarter, revenue grew 32% versus the first quarter, 2022, and in the first, half of the year, we have already surpassed the total revenue generated in this region last year. In Latin America, there are over 250 patients on reimbursed therapy. This will continue to grow as we continue expanding in Brazil and as we gain momentum, from our recent launches in Colombia and Mexico.

What our expectations are what the challenges are.

In Argentina, we continue to support named patient requests and look forward to gaining, regulatory approval over the coming quarters.

Across all of the Ultragenyx regions, prosperity revenue in the first half of 2022 grew 37% compared to the first half of 2021. Based on our performance to date, we are reaffirming our 2022 revenue guidance in Ultragenyx territories, of $250 to $260 million.

Turning now to the JOVI and beginning with our efforts in the U.S., we continue to see, steady growth across all of the leading indicators as a result of the broad use in key metabolic genetic clinics across the U.S. One of the more promising statistics is that approximately 90% of all cases are approved, for reimbursement in less than 30 days.

This is an even faster turnaround time than we saw for PROSFETA at a similar stage of, commercialization.

At this point in the year, we are reaffirming the guidance of $55 to $65 million that we, put out in January.

Thanks, Jeremy Yes, you heard correctly penetration is 15% and the adult market versus 40%.

The team is also moving beyond the major centers for inborn errors of metabolism and is expanding, the call coverage to other high potential healthcare professionals.

I look forward to providing another update on this and other commercial programs next, quarter.

We are leveraging machine learning and artificial intelligence to generate new leads similar, to what we are doing for PROSFETA.

With that, I will turn the call over to Marty to share more details on the financial results, for the quarter.

Outside of the U.S., use of the JOVI continues to add new physicians and patients through, our named patient and early access programs in Europe.

Thanks, Eric.

In France and Italy, there continues to be meaningful demand through our named patient, program and we are starting to respond to requests for named patient programs across other countries in Europe.

In Brazil, the health authorities approved the JOVI for the treatment of both pediatric, and adult patients with LC-FAOD late last year.

CRISPIDA revenue in Ultragenyx territories was $64 million, including $51.6 million from, the North America Profiteer Territory and net product sales of $12.4 million in other regions.

We are continuing to work through the process to get full reimbursement approval, but this, can take a little bit of time to complete.

Total royalty revenue related to the sales of CRISPR-Vita in the European territory was $5.4 million.

The Jolvi revenue for the second quarter, 2022, was $13.5 million.

The pediatric market and the adult market represented represents about two thirds of the overall prevalence. So there is a significant growth opportunity with adults. It just takes longer to to pull through because and as I've stated many of these patients a loss in the system.

Mpsevi revenue for the same period was $4.9 million.

Physicians being treated for signs of symptoms related to <unk>, but not necessarily <unk>, excluding XL H, but one thing is I'm going to say that when we do find them. We are able to convert them at a very high rate and they stay on therapy.

We do offer genetic counseling.

Which which does.

<unk>.

Family <unk> work and the work we've done to date, we think we are.

There are about two to four family members for each <unk> program. So for each patient that's been identified they're about two to four on average that we're finding when patients take advantage of genetic counseling and fairly pre analysis.

So that is something that we will deleverage.

Thank you.

Our total operating expenses for the second quarter, 2022, were $230.9 million, which includes research and development expenses of $154.5 million, SG&A expenses of $68.1 million, and cost of sales of $8.3 million.

Our next question comes from Joel Beatty of Baird. Your line is open.

Hi, Thanks for taking my questions.

With the new cash on hand from the recent deal what are your plans for this cash.

Well thank you.

Marty you want to answer sure yes, yes, thanks, Joe so.

We are well-capitalized with over $1 billion in the bank, and we are making operating decisions to stage spend on our development programs, and slowing headcount growth in order to manage our burn.

For the cash are while we used a little bit already to acquire genetics of course with a $75 million that really the cash on hand, and now that we have over 1 billion in the bank. We feel really good that this is going to fund our development program and really put us on this great pathway to profitability.

A little bit more refined we have some very.

Meaningful milestones over the next few years and clearly the cash will get us through those.

Those milestones. It also allows us to maintain flexibility in terms of how and where we operate and I shouldn't balance that and I think I said this in our script as well.

Is that we have a lot of <unk>.

<unk> and employing a lot of discipline in how we spend it.

We are managing our head count growth is slowing the rate of growth there and I should say.

As we have said, 2022 is a peak burn year for us as we have initiated multiple late-stage clinical programs, in-licensed at KISA, completed the acquisition of genetics, and are completing the build-out of our gene therapy manufacturing facility.

In 2023, we don't anticipate additional one-time events of this nature or large capital expenditures, and we anticipate SG&A will decrease compared to 2022 as we transition U.S. and Canadian commercialization responsibilities for Crisp Vita to KKC.

Net cash use.

Just reiterate once again.

This is a peak year for a number of one time expenses acquisitions and in licensing and the startup of a number of programs et cetera.

We look forward that the net cash use will.

Continue to decrease over time.

So it puts us in good shape moving.

Moving forward.

Great. Thank you.

Thank you. Our next question comes from Dae Gon Ha of Stifel. Your line is open.

For the second quarter, June 30, 2022, net loss was $158.2 million, or $226 million per share. During the first half of the year, there have been a number of non-cash items that have impacted net loss. This includes approximately $65 million of stock-based compensation, $20 million related to the decline in fair value of our equity investments, and $13 million of non-cash interest expense related to the Royalty Pharma transaction. These are offset by approximately $10 million of non-cash revenue, also related to the EU royalty.

We ended the quarter with approximately $706 million in cash, cash equivalents, and marketable securities. Subsequent to the end of the quarter, in July, we raised $500 million in non-equity dilutive capital, in a non-equity dilutive capital transaction with Omer's Capital Markets for the sale of a portion of our North America Crispita Royalty.

We also exercised our option to acquire genetics and paid $75 million in July, which allows us to take over the development of GETX 102.

We are well-capitalized with over $1 billion in the bank, and we are making operating decisions to stage spend on our development programs, and slowing headcount growth in order to manage our burn. As we have said, 2022 is a peak burn year for us, as we have initiated multiple late-stage clinical programs, in-licensed EPGISA, completed the acquisition of genetics, and are completing the build-out of our gene therapy manufacturing facility.

Great. Good afternoon, thanks for taking our questions.

Two from US one on one or two.

When the commentary or I guess guidance for the next update is contingent upon substantial data.

Given that it's more of an individualized dosing on a per patient basis can you maybe walk us through what that substantial data definition would be also because longer term.

Duration of follow up seems to correlate with better functional improvements and then second question for Marty as we think about that I guess $1 billion, plus and the net cash burn.

We will continue to invest in our clinical and preclinical programs as discussed, and the overall net effect across the company then will be a decrease in net cash burn.

Seemingly coming down I guess can you maybe walk us through some of that sensitivity like what kind of factors into.

Our cash runway of five years versus say.

<unk> profitability. Thanks.

Now I'll turn the call over to Camille.

Yes.

Sure I'll start Marty you can deal with the cash question. So on okay. What we're talking about in our next data output I think we want to be clear that we're not going to just release.

Three or four patients worth of data at the next cohort as the next plan will be operating the dose escalation cohorts will then expand that cohort and treat.

Our larger number of patients and what we said it will come out when we treat enough patients to give us a substantial efficacy result that we can speak to and that people can be confident in.

Rather than.

Small bits of data going forward, we think the mid year update was very important because it put forth to clarity that we can dose of this drug and that you can do it without having drug related safety events and that we are seeing efficacy. So that means we're in the game and we have an opportunity now to demonstrate clinically meaningful results that we saw before.

And we're clearly seeing as we've talked today quantitatively, but the next time you want to talk about I want to make sure. We have a substantial amount of data that will provide confidence to all that we are in the right direction towards heading towards phase III.

Yes.

I will comment a little bit more on the runway for you.

No we don't give specifics about when we'll be cash flow positive.

We will continue to invest in our clinical and preclinical programs as discussed, and the overall net effect across the company then will be a decrease in net cash burn.

But what we did say just to reiterate that this does put us on a pathway towards profitability.

Now I'll turn the call over to Camille.

And given our growth in revenues and our increased number of development.

Thank you, Marty, and I too wish everyone good afternoon.

This is truly an exciting time for clinical development at Ultragenyx.

We have seven programs in the clinic, including our ASO for Angelman syndrome that Emil discussed earlier, an mRNA for glycogen storage disease type 3, four late stage gene therapy trials, and a phase 2, 3 monoclonal antibody for osteogenesis imperfecta.

Moving forward, we do see our net cash used coming down as I've said, many times, but those development programs also gave us a lot of flexibility and levers to pull if we need to.

Manage our net cash burn forward.

That's a lot of flexibility and levers to pull.

If we need to.

Manage our net cash burn forward and to get towards.

Ultimate goal would be to be cash flow positive and towards profitability.

So I don't know Doug Doug if you want any more specifics, we're not going to give a year specifically, but importantly, we feel like we're in a good a good cash position.

Prudent going forward levers to pull to help manage the cash flow going forward and increasing revenues. So we feel like we are in it.

Good position financially to move forward.

In my section on today's call, I will focus on this antibody, UX143, or cetrusimab, that we are developing for osteogenesis imperfecta. Osteogenesis imperfecta, or OI, is caused by a defect in collagen that results in significant bone weakness and bone fragility, leading to fractures, deformities, stiffness, and pain.

Thank you, Marty, and I too wish everyone good afternoon.

This is truly an exciting time for clinical development at Ultragenyx.

Okay, great. Thank you very much.

We have seven programs in the clinic, including our ASO for Angelman syndrome that Emil discussed earlier, an mRNA for glycogen storage disease type 3, four late-stage gene therapy trials, and a phase 2-3 monoclonal antibody for osteogenesis imperfecta.

Thank you. Our next question comes from <unk> of Bank of America. Your line is open.

Currently, there are no approved therapies for OI. As a company, we have spent a lot of time studying bone biology with XLH, TIO, and our preclinical candidate for OI before we did the deal for cetrusimab.

In my section on today's call, I will focus on this antibody, UX143, or citruzumab, that, we are developing for osteogenesis imperfecta. Osteogenesis imperfecta, or OI, is caused by a defect in collagen that results in significant, bone weakness and bone fragility, leading to fractures, deformities, stiffness, and pain.

One of our key insights is that OI is not simply an issue of weak collagen. It is excessive bone resorption and the inadequate production of new bone triggered by this abnormal collagen that leads to low bone mass. What we have found is that if you can increase bone formation and reverse the excessive bone resorption, you can improve bone strength, even with the abnormal collagen, and improve fracture prevention.

Currently, there are no approved therapies for OI. As a company, we have spent a lot of time studying bone biology with XLH, TIO, and our, preclinical candidate for OI before we did the deal for citruzumab.

We believe this insight gives us the opportunity to change the future for patients with osteogenesis imperfecta.

One of our key insights is that OI is not simply an issue of weak collagen. It is excessive bone resorption and the inadequate production of new bone triggered by this abnormal, collagen that leads to low bone mass. What we have found is that if you can increase bone formation and reverse the excessive bone, resorption, you can improve bone strength, even with the abnormal collagen, and improve fracture prevention.

I won't take time today to go back through all the details of the Phase IIb asteroid data that Mario has already presented.

We believe this insight gives us the opportunity to change the future for patients with osteogenesis, imperfecta.

I won't take time today to go back through all the details of the Phase IIb asteroid, data that Mario has already presented.

Thank you for taking my questions.

I do want to remind you of a few of the most important points.

I do want to remind you of a few of the most important points. This trial was a large, randomized, blinded study of 90 adult patients with OI being studied, across three different dose levels. After 12 months, the results indicated dose dependent and statistically significant effect, on bone formation and bone mineral density. Furthermore, the substantial bone mineral density improvements occurred across multiple, anatomical sites.

The minor on Angelman.

This trial was a large, randomized, blinded study of 90 adult patients with OI being studied across three different dose levels. After 12 months, the results indicated dose-dependent and statistically significant effect on bone formation and bone mineral density. Furthermore, the substantial bone mineral density improvements occurred across multiple anatomical sites, and the observed substantial bone formation, we believe, is a very important factor in improving bone strength.

And the observed substantial bone formation, we believe, is a very important factor in, improving bone strength. All of these findings were accompanied by a favorable safety profile.

So.

When do you anticipate Ashley discussing with SBA.

About trying to.

Similar to how we developed borosimab for XLH when we took over development from KiroKirin, we are taking these impressive cetusimab results in adults with OI and looking to further improve upon them for pediatric patients.

All lines of the protocol that you've got ex U S with the U S.

And as it relates to dosing.

Currently, we are enrolling and dosing patients with OI between the ages of 5 and 25 years, with the goal of using the Serum Bone Formation Marker, P1MP, to optimize the dose.

Once we have determined the pediatric dose strategy, we will transition directly into, Phase 3, evaluating the benefit of cetusimab on fractures.

Think that ultimately you may want to try this dose to where you had been dosing originally just set a slower titration. So.

With this update, I will now turn back the call to Emil.

Thank you could want to go to lets say 36 months.

And how long could that tank, if thats something thats on the table.

Yes.

Our plan in the U S alignment <unk> top priority and we have enough data now we think we just.

We were asked to provide it in the CSR format, which were doing which requires a bit more effort. We are doing that effort right now, which we would hope to get that submitted in skip U S patient going this year because it would certainly help us as we expand so that would be our goal to get them going this year and to be part of that expansion.

That's our plan in the U S. I've had numerous conversations and we are continuing to.

To talk with the division in various ways and.

We believe we can get that done now.

Now with regard to the dosing.

I don't think we need to go to 36, I think we already remember that number originally with what happened with based on single dose data and the monkey to knockdown you can get to a single dose, which you don't need it you can get to near maximum knockdown with giving the equivalent of.

The equivalent of 10 milligrams three times so.

I honestly don't think it's necessary to get there.

I don't think we've loaded quite enough yet, but I also would say if you looked at the quantitative data we were just talking about in our deck.

And you'd see that actually from a quantitative data with the Bally were actually at a very similar place where we were so I don't think were so far off I think getting into the 10 range, it's going to get us where we need to go once we give multiple doses of it.

So right now I would not I don't think that's necessary I think we can get there where we are and therefore, just we need to give it multiple times and we need to give it enough time to act, but I don't think going up to 36 necessary.

Okay. Thanks, Raimo and just to clarify about your discussions with FDA will you need do you feel like you'll need to have more confidence on what the final dosing regimen should be collect all the information that you are collecting now before you go meet with FDA or does it not matter.

No. Our feeling was we have enough data to enter the clinic and include U S patients in the dosing program that we're doing right now that we can dose levels. We're at but we're doing it carefully you can monitor and not seeing any any drug related safety event. So the point is to get the us involved in that dose determination.

All of these findings were accompanied by a favorable safety profile.

<unk> phase not afterwards, so I don't think I think there are concerns were a number of questions about certain assays and things are let's say certain.

Currently, we are enrolling and dosing patients with OI between the ages of 5 and 25 years with the goal of using the Serum Bone Formation Marker, P1NP, to optimize the dose.

Once we have determined the pediatric dose strategy, we will transition directly into, phase three, evaluating the benefit of statuzumab on fractures.

With this update, I will now turn back the call to Emil.

Iology, which we've now shown are do not occur.

And the fact that we've been able to dose safely with the new administration strategy.

The number of elements of what we have should be sufficient to open the door to including the U S. In the dose titration part of the study as well as going forward. So we're going to work to get that done as promptly as we can and get those patients in the U S.

In the program this year.

Thank you.

Okay, great. Thank you.

Okay.

Emil, we're having a little bit of a hard time.

Thank you. Our next question comes from Cory <unk> of <unk>.

I'm happy to finish this out.

Thank you.

No, I'm fine.

Emil, we're having a little bit of a hard time.

J P. Morgan your line is open.

I just have a problem with my phone, but I'm fine now.

Alright.

Thank you.

I'm happy to finish this out.

Thanks for my question I was just wondering if you could provide any incremental color on the re dosing of the original five angelman patients.

So, thank you, Emil.

No, I'm fine.

Before we shift to the Q&A portion of the call, I'll provide a quick reminder of the, key upcoming milestones. For UX143 and oxygenesis imperfecta, we'll continue enrolling patients in the phase two, portion of the study and expect to provide an update on the dose strategy for the phase three portion around the end of the year.

I just have a problem with my phone, but I'm fine now.

In our gene therapy pipeline with UX111 for sample EPO, we are continuing to follow patients, who have been dosed in the pivotal study and continue to evaluate the feasibility of filing for approval based on convincing biomarker data.

Separately, we expect to initiate a study in children under five years old in the second, half of the year.

Around their dosing paradigm.

Data would be included in the next readout. Thanks.

Thank you.

So, thank you, Emil.

Yes, so I think it's very important thing we've been pursuing this because those patients wanted to get re dose so.

Before we shift to the Q&A portion of the call, I'll provide a quick reminder of the, key upcoming milestones. For UX143 and Osteogenesis Imperfecta, we'll continue enrolling patients in the Phase 2, portion of the study and expect to provide an update on the dose strategy for the Phase, 3 portion around the end of the year.

We'll continue to roll in the phase 3 for DTX401 and first stage of the UX701 study.

Separately, we expect to initiate a study in children under 5 years old in the second, In our gene therapy pipeline with UX111 for SAMHSA-Lipo, we are continuing to follow patients who have been dosed in the PIVL study and are continuing to evaluate the feasibility of filing for approval based on convincing biomarker data.

We wanted to give them an avenue given them, we're unable to do that in the U S. At this point in time.

We're able to get.

One good site for us in Canada to dose and what Theyre doing is theyre dosing at the same cohort for cohort five.

Regimen, right, which is three three dose for the young patients and it would be five dose for someone who is eight or older.

Alright, so it's going to be that that same ladder of dosing that we used in cohort four and five that what theyre going to get started with <unk>.

We also expect to finalize start-up activities for DTX301 and begin dosing patients later, this year. On the manufacturing side, we'll continue to build out of our facility in Bedford, Massachusetts, which is on track to begin producing material in the first half of 2023.

So the first patient has been dosed.

The second one and signed up.

We'll continue enrolling the phase three for DTX401 and first stage of the UX701 study.

We will try to get as much as we can done that way until we hopefully get the U S open and get the patient actually back in the U S. But as we noted the first patient hasnt dose safely did well did not have a problem no drug related safety issues, So which is what we expected there was no reaction to the drug based on our history of exposure.

For UX053 and glycogen storage disease type three, in the second half of the year, we, expect to share single dose data from the first part of the phase one two study and initiate the repeat dosing stage.

For UX053 and Glycogen Steroid Disease Type 3, in the second half of the year, we expect, to share single-dose data from the first part of the phase 1-2 study and initiate the repeat dosing stage.

For DTX102 and Angevin syndrome, we're also continuing to enroll cohorts six and seven, at seven and a half or 10 milligrams outside of the U.S. Our expectation is to provide the next update once we've determined an optimal dose and, have gathered substantial data from the expansion cohort.

For DTX102 and Angevin Syndrome, we're also continuing to enroll cohorts 6 and 7 at 7.5, or 10 milligrams outside of the U.S. Our expectation is to provide the next update once we've determined an optimal dose and, have gathered substantial data from the expansion cohort.

All these programs create a distinct opportunity to make meaningful difference for patients, and are the reason we believe we have one of the most robust, diverse, late-stage pipelines. In rare diseases.

So which was what all the biology said would be true. So we're happy that got started.

With that, let's move on to your questions.

Said, though that it's taken so long to get these kids back on because they are just aching to get back on because all the stuff that was the benefit they saw before I just want to get back to it. So we've got to get to them soon as we can.

Great. Thank you.

Operator, please provide the Q&A instructions.

With that, let's move on to your questions, Operator.

Thank you. Our next question comes from Yaron Werber of Cowen Your line is open.

Thank you.

Please provide the Q&A instructions.

Ladies and gentlemen, if you'd like to ask a question, please press star 11 on your, touchtone telephone.

Again, if you would like to ask a question, please press star 11.

Thank you.

Sure.

Two quick ones on insulin than one zero 53, so just <unk>.

Ladies and gentlemen, if you'd like to ask a question, please press star-11 on your touchtone, telephone.

Again, if you would like to ask a question, please press star-11.

One moment, please.

Our first question comes from Gina Wang of Barclays.

Alan I assumed the FDA just wanted to look at the clinical site reports right theyre not necessarily waiting for lids.

Your line is open.

I have two quick questions.

The first one is for Chris Vitti.

Elizabeth aircrafts to have natural history from the for controls.

I just wanted to make sure I heard it correctly.

If that's the case, I'm wondering how would you expand the adult market share and how, active you are to leverage FamilyTree?

And the second question is regarding the Endowment Program.

And then secondly, if you do.

If youre, considering obviously doing in MDI as an endpoint also as opposed to let's say.

Once you choose the dose.

Planning to expand the study maybe you have a placebo just to kind of have some experience with that before we go into phase III and then I have actually a question separately on 53.

One moment, please.

Hey.

The controls were not really part of the safety story, there a part of assessing efficacy in those controls have gone through their day 120, we just didn't have that data.

At the time of the.

The release before so we can include that information, but I think the more important information was.

The dosing administration safety in detail in our CSR.

Clinical study report format GTP compliant Reg compliant format. That's what we were at four so we will be doing that on the <unk> data and will provide the U S data and update but I think that the <unk> is more important in this state.

And the control information will be in there.

I think it's since earlier this week, update, I wanted to know that the expansion cohort, that will still be a definition, the clinical benefit will be two score in two domains.

With regard to the MDI <unk> multimedia responder index, and we will look at multiple domains will analyze the data we have by the method.

And are you willing to open to those higher than 14 milligrams?

As we get there but the.

The expansion, we're planning to do once we hit our dose will help us get a little more insight into the dose and how good it is and how have we really optimize it for all types and maybe.

Providing more color on.

The youngest patients versus the oldest patients and how the dose banding should be really conducted for a trial.

Okay.

Let me ask the second one first, and then, Eric, you can touch on this Chris Vitti adult, needs penetration question.

With regard to adding a control group.

So, on the expansion, we're still using the 2 plus 2 main to set as criteria for titration.

And we expect that we're going to be very close to where we need to be.

I guess, there's a lot of interest now and what's the magnitude of change seems to be a theme.

I'm not sure why there is so much interest in it I think we could add that kind of control group, but it does make things complicated I think the question. Your own is whether you believe the amount of data or the size. The magnitude of the effect. We will have is incredible real effect or whether youre, believing those just placebo and I would say to you the magnet effect where thing is <unk>.

In fact, we're going to be looking at all their efficacy results, including the longer, term results, also to tell us a little bit more about where we're at.

But that's what we expect.

We don't expect to have to go beyond 14, frankly.

I think we're very close.

Nearly beyond placebo and were comfortable that it is.

As we get to the optimal dose your own will have more data to say about what that effect is in this magnitude.

And our hope to be there it would be clear.

So right now, I wouldn't speculate on that.

If a control group would help we can look and think about that but right. Now I think we're looking for hopefully a incontrovertible large effect, which is I think where we're on a we're on track to do.

I don't think it's going to be necessary once we start loading at this next cohort level.

But we'll want to make sure we do get the dose right.

Right I guess.

Look if it's a two point difference at 24 weeks I mean, it's one thing if it's <unk> nine or one one I'm, just making numbers up random numbers obviously.

It's obviously a little bit of a different discussion I'll also not just for us obviously for regulators more importantly.

Yes, and then for you in terms of how do you power a new endpoint for pivotal.

And while I'm jumping in it looks like your phone might have clicked off again.

Yes, Unfortunately, my phone when it goes on whatever.

Sleep screensaver motive it basically turns off it appears so.

So, we'll continue to evaluate what we're seeing, both in the CGI score, but also in, the quantitative scores, and also over longer periods of time to make sure we're getting to a dose level that will provide us a substantial, meaningful clinical benefit that we could study in phase three.

Sorry for that.

So M&A.

In any case I don't know when you'll ask me, but.

I don't think I think we should be seeing.

Sure.

We should be seeing substantial data that would make us confident that it's not placebo and I actually think for thing already are you re.

Now for the penetration, I think we've been talking about the challenges of finding adults, with Crescida, but the good part is when we find them, they do get prescribed.

So Erik, maybe you can touch on the issue she's asking about with regard to penetration, of the adult market, 15% versus P's where it's much higher, and what our expectations are and what the challenges are.

<unk> I've seen I've run the Bally and all kinds of blinded placebo open label trial.

Thanks, Camille.

Yes, you heard correctly, penetration is 15% in the adult market versus 40% for the pediatric, market.

And the adult market represents about two-thirds of the overall prevalence.

Never seen things move beyond the variability of the test before we're seeing movements. There are significant beyond just the variation of the test already and I think thats just not something you see normally so I'm confident we're well past that and I think the quantitative data or actually a little more meaningful because they are an absolute <unk>.

So there is a significant growth opportunity with adults.

It just takes longer to pull through because, as I stated, many of these patients are lost, in the system of community physicians being treated for signs and symptoms related to, XLH, but not necessarily XLH treating the XLH.

But one thing, as Amos stated, when we do find them, we're able to convert them at a, very high rate and they stay on therapy.

We do offer genetic counseling, which does pedigree family-free work.

In the work we've done today, we think there are about two to four family members for each, XLH program.

So for each patient that's been identified, there are about two to four, on average, that, we're finding when patients take advantage of genetic counseling and family-free analysis.

<unk> rather than a feeling about how they are changing so.

So that is something that we do leverage.

We're excited by what we're seeing your own I don't think we will need a placebo to make the call for phase III, but I understand the question, which is how confident will we be that what we're seeing is a real effect that will stand withstand the placebo controlled trial in Europe sensors, having some control.

It actually help us making that call. So I appreciate that point.

Yes.

Placebo, if you look at average data, which you know well really.

Less than a point of the year so.

And then maybe you can just a quick question and I apologize for all these questions on marathon zero 53, four for Juicy three dosing IV Q2 weeks or so.

Is there a chance to think about going sub Q and then secondly, just given whats the tolerability, so far and I know, it's very early given it's an mrna therapeutics. Thank you.

It's very early I don't want to go into the details yes. It's very early in the program bar expectation is more likely to go once a month dosing not not every two weeks out of the limit edge of the thing our plan is to be once a month, we think once a month will be enough because in this case, we need to clear the abnormal.

Dexter and limit dextran storage material once you've cleared it doesn't accumulate that fast as you can clear it.

Even it doesn't matter if the drug it's faded away. After two three weeks you still will be okay for a couple of weeks and then conclude again that makes sense.

It has to be completely clear continuously to get the benefit of the drug. So we are looking for monthly and we wouldn't necessarily go to sub Q, but certainly it hasnt done sub Q before.

Great. Thank you so much alright.

Our first question comes from Gina Wang of Barclays.

Thank you.

Thank you. Our next question comes from <unk> Richter.

Of Goldman Sachs. Your line is open.

Your line is open.

Our next question comes from Joel Beatty of Baird.

Hi, This is Tommy on first Halloween. Thanks for taking our question we have two on Angelman. So the first is that it seems based on the interim update that the younger patients benefited more and were wondering how much of this do you think might be due to the drug needs to be given earlier that patients with.

I have two quick questions.

Your line is open.

Hi.

<unk> develops naturally like more quicker to younger age versus when they are older and secondly about the phase III study.

Do you have any guidance on when this might begin would you wait for the differentiator fees to align under the same protocol or could you see a.

Similar designers in the phase one two whereas the dosing protocol is different from geography.

First one is Chris Vitti.

Thanks for taking the questions.

Just wanted to make sure I heard it correctly, that you manage a 15% adult market.

With the new cash on hand from the recent deal, what are your plans for this cash?

If that's the case, I'm wondering how would you expand the adult market share and how, active you are to leverage family tree?

Well, I think maybe, Marty, you want to answer?

Sure well first question I think it's pretty clear even from the FERC five original five patient currently now that the younger patients.

And the second question is regarding the Andrew Mann program.

Sure.

Benefit more rapidly certainly that part is.

Clearly they definitely get better more quickly I think it's also a factor potentially of dosing that is theyre getting a dose that for them is higher than it was for the others. So in the <unk>.

Current cohort before you're all really look the best but the core of <unk> getting a doses.

Relatively higher than the <unk> seven years old right and it is much bigger so I do think it is just an indicator of both the dosing it could be age being earlier, but we've seen improvements and even the 13 year old showed some nice improvement so.

I don't think Asia is going to stop us completely from getting good effect I think we're going to see it it may be in different domains, but I still think we're going to see good effect in all of them I think we just need to make sure. The dosing is optimized and not just flat I think it is going to have to be adjusted for age.

I think since earlier this week update, I wanted to know that the expansion cohort, that would still be a definition.

The clinical benefit will be two score in two domains.

Now with regard to the phase III, our plan would be to get the U S involved in the phase II study certainly would need a synchronized global phase III, we would not want to have a separate ex U S. In the U S Phase III program I don't think Thats. The smart move we think we can get the U S. On board I think they are being conservative at the moment, but I think we can put.

<unk> information, they require and get them onboard.

Get the patients going in phase II.

Ultimately phase III.

Yeah.

Thank you. Thank you our next question.

Yes.

Our next question comes from Maury Raycroft of Jefferies. Your line is open.

And are you willing to open to those higher than 14 milligrams?

Thanks, Joel.

So our new plans for the cash are, well, we used a little bit already to acquire genetics, of course, for the $75 million.

But really, the cash on hand, and now that we have over a billion in the bank, we feel, really good that this is going to fund our development program and really put us on this great pathway to profitability.

A little bit more refined, we have some very meaningful milestones over the next few years, and clearly the cash will get us through those milestones. It also allows us to maintain flexibility in terms of how and where we operate.

Okay.

So we're managing our headcount growth and slowing the rate of growth there.

But I should balance that, and I think I said this in our script as well, is that we have, a lot of prudence in employing a lot of discipline in how we spend it.

And on for Maury.

And I should say, net cash use, just to reiterate once again, this is a peak year for a number, of one-time expenses, acquisitions and in-licensing, and the start of a number of programs, etc.

And we look forward that the net cash use will continue to decrease over time.

Just to clarify how much time gap is needed to address the next group of expansion patients. After the first two patients had been dosed in core six or seven.

Okay, let me ask the second one first, and then, Erik, you can touch on this CRISPR adult, peds penetration question.

Okay. So the way the protocol work as the first two patients in each cohort there are two doses and we assessed where theyre going.

So on the expansion, we're still using the 2-plus-2 main to set as criteria for titration, and we expect that we're going to be very close to where we need to be, in fact.

We're going to be looking at all their efficacy results, including the longer-term results, also to tell us a little bit more about where we're at, but that's what we expect.

We don't expect to have to go beyond 14, frankly.

I think we're very close.

So right now, I wouldn't speculate on that.

<unk>.

They are you should be titrated that'll get titrated, then right away. The next cohort will begin while the first.

I don't think it's going to be necessary once we start loading at this next cohort level.

But we'll want to make sure we do get the dose right, so we'll continue to evaluate, what we're seeing both in the CGI score, but also in the quantitative scores and also over longer periods of time to make sure we're getting to a dose level that will provide us a substantial, meaningful clinical benefit that we could study in Phase 3.

Now, for the penetration, I think we've been talking about the challenges of finding adults, with CRISPR, but the good part is when we find them, they do get prescribed.

So Erik, maybe you can touch on the issue she's asking about with regard to penetration, in the adult market, 15% versus P's, where it's much higher, and what our expectations are and what the challenges are.

Thanks, Emil.

Six and seven are getting their second two doses. The next cohort will begin right away. So there is a little faster turnaround now in terms of dosing up.

Does that help.

Okay. It makes sense, Okay, and then a quick question on the Williston how is the pace of enrollment and do you think you can get stage.

Stage, one data escalation at this stage to pivotal by year end up more like an immediate uptick.

Yes.

As we've said before the <unk> in the 701 or both and program. The FDA required a staged enrollment which was separated by several weeks before between each patient.

There wouldn't be possible to get through all of the enrollment in that timeframe and get their enrollment has begun and we are enrolling patients, but it would it basically stretches out the time of the enrollment for the phase one part of the program significantly so it won't have data on Wilson by year end.

We will provide an update when we can but.

So, it puts us in good shape, Joel, moving forward.

We are out there we're moving forward so.

Great, thank you.

It will take a little bit more time before we see phase two data from 701.

Thank you.

Thank you. Our next question comes from Joon Lee of <unk>. Your line is open.

Yes, you heard correctly.

Our next question comes from Dagon Ha of Stiefel.

Penetration is 15% in the adult market versus 40% for the pediatric market.

Your line is open.

And the adult market represents about two-thirds of the overall prevalence.

So there is a significant growth opportunity with adults.

It just takes longer to pull through because, as I've stated, many of these patients are, lost in the system of community physicians being treated for signs and symptoms related to XLH, but not necessarily XLH treating the XLH.

Okay.

But one thing, as Emil stated, when we do find them, we're able to convert them at a, very high rate and they stay on therapy.

The updates regarding gtx, one to one or two.

We do offer genetic counseling, which does pedigree family tree work.

And the work we've done today, we think there are about two to four family members for each, XLH program.

So for each patient that's been identified, there are about two to four on average that, we're finding when patients take advantage of genetic counseling and family tree analysis.

So that is something that we do leverage.

State your comment that 10 milligram in preclinical models using a complete lockdown of the antisense, but do you have any evidence that it's actually.

Going to a meaningful Ub create expression.

Correct me, if I'm wrong, but I'm not aware of any <unk> three expression data in animal models. That's been publicly disclosed. Thank you. Yes June it does induce either we wouldn't be talking about if it didn't.

Thank you.

Our next question comes from Joel Beatty of Baird.

Your line is open.

<unk> expression and particularly for us because our secrets from August the monkey. So we can get a direct result of the monkey.

Unlike other situations so.

Because we are a direct result, we also have turned out there is a single nucleotide polymorphism and <unk> in monkeys, which will help us in some hana from individual monkeys.

The distinguished between the <unk> coming from the maternal run versus the paternal chromosome.

And those animals, we can look for the SNP in the paternal expression of the gene right and that allows us to determine that we're getting paternal expression in the monkey and we have in fact verified Ub great expression.

At that dose level.

Can you quantify that that'd more quantifiable.

Context.

Well what happens when you get that expression you end up getting autoregulation, so you'll end up getting.

Very similar levels between mature.

Alright, so thorough at 50 50.

Okay, great. Thank you.

Hi.

Great.

Thank you. Our next question comes from Lisa <unk> of Evercore ISI. Your line is open.

Thanks for taking the questions.

Good afternoon.

With the new cash on hand from the recent deal, what are your plans for this cash?

Hi, Thanks for taking my question.

Thanks for taking our questions.

Two from us.

One on 102, Emil, when the commentary, or I guess guidance, for the next update is contingent, upon substantial data, I guess, given that it's more of an individualized dosing on a per patient basis, can you maybe walk us through what that substantial data definition would be also because longer term duration of follow-up seems to, I guess, correlate with better functional improvements?

Just on the Angelman MLR do completely.

And then second question for Marty, as we think about that, I guess, one billion plus, and the net cash burn seemingly coming down, I guess, can you maybe walk us through some of that sensitivity?

Like, what kind of factors into, say, a cash runway of five years versus, say, till profitability?

Thanks.

Sure.

Understand or was it wasn't totally tracking with the bally's versus CGI and why that's so.

I'll start, Marty, and you can deal with the cash question.

So much more convincing and kind of like the cycling out the noise can you maybe just speak to that again.

So, on what we're talking about in our next data output, I think we want to be clear that, we're not going to just release, you know, three or four patients' worth of data at the next cohort, as the next plan.

We'll be operating the dose escalation cohorts.

We'll then expand the cohorts and treat our larger number of patients. And what we said is we'll come out when we've treated enough patients to give us a substantial, efficacy result that we can speak to and that people can be confident in rather than small bits of data going forward.

We think the mid-year update was very important because it put forth the clarity that we can, dose this drug and that you can do it without having drug-related safety events and that we are seeing efficacy.

So, that means we're in the game and we have an opportunity now to demonstrate the kind, of clinical results that we saw before and we're clearly seeing, as we've talked today quantitatively.

But the next time we want to talk about it, we want to make sure we have a substantial, amount of data that will provide confidence to all that we are in the right direction toward heading toward a phase three.

Well the CGI proven scale is a relative scale word docs as minimal plus one plus two plus three it's very sensitive because they're trying to comparable before to after straight up and usually the quantitative they're harder to move because they require a therapist to act and do conduct.

Specific things that the Kid has to do in order to score right in order to move them forward.

<unk> tends to be more rigorous in Oman, and a stronger measure of the absolute change, whereas the other test can be somewhat dependent on the investigator and their view of what minimal is or what moderate what mushrooms. Okay. Yeah. So when you're trying to look across investigators in the study I think looking at the quantitative kind of gives you an.

Yeah.

Objective.

What's different right.

That's why I think it's a little better that's why we're showing this comparison of quantitative because we're trying to show okay with different investigators. The bally. It's the same test done the same way by different people, but it's still a therapist doing the test and therefore I think is a more comparable way of comparing sites.

Okay.

And then.

With the Bally's, if it's kind of that as you said more quantitative as the I'm just trying to think of as the kids are just like naturally.

I am sure. They are acquiring skills just at a lower rate does that how does that factor into your kind of thinking on sort of the background rate of change.

On the Bailey.

Sorry, ammo youre on mute again.

Alright.

My phone went off.

Alright.

The yes, so the Bally it's been studied in the natural history. It doesn't change I don't know coming up do you have anything to say about the daily but I thought it was in that number of natural history programs and not changing none the development really changes in the severe pain.

Yes, that's correct. Thank you Emil. Thank you also Lisa for the question.

The daily in particular communication is quite.

Flat over time and in particular in individuals with <unk> deletion mutation and those are the patients. We're studying at this time there are a number of references that illustrate T relative flatness of improvement in in these measures and we act.

We have one of those references sited.

In our.

Corporate deck.

And we're happy to follow up with you also on that.

Okay. Thank you and then just to now takes us into phase III. So I think you were thinking about the multi domain.

This endpoint so would there be some combination of bally and CGI and other things or how should we be thinking about that.

Well the amongst you mean responded it would use only quantitative measure like Bailey.

The Bally receptive expressive could be a communication domain and we'd look at those two and measure communication change we could use daily for the gross motor change as well, we could do a different measure for sleep.

Like in ancient severity score for sleep.

So.

There'll be a quantitative test for each domain and we will have to set a minimum amount of change in order to be considered clinically meaningful in order to do the multimedia responder type approach.

The value of that of course is that there is some heterogeneity, we can capture benefit across multiple domains. It's a lot more powerful.

Type of analysis.

Im very type of analysis is really tenfold more powerful than other types.

For many of these complex multi domain disorders.

Okay and I have two more questions is that okay. They are relatively quick.

One is beginning questions on <unk>, and like where it kind of fits into the treatment paradigm given there's some.

Some other kind of treatments that can be used can you maybe just.

Explain how you are thinking about the target product profile and kind of where would it fit in the context of payment.

Treatment today.

Yes, I'll just do that look.

Look I think there's a lot of anti resort.

That are this phosphate raw related compounds that have an effect on resorts in but they don't improve bone production. Therefore, there arent really improving bone strength of trying to reduce the amount of excess absorption.

In the five randomized studies only two of them were positive and the magnitude of effect with a 20% reduction in fracture. So it makes patients feel better but it doesn't solve their fracture problem really and so we think that there are a lot of room for improvement there with regard to other biologics that are maybe looked at I think the truth of the matter where the insight.

Score Austin is really by far the best in terms of its phenotype of inducing bone cells to become bone producing cells <unk>.

The last two to ask you two of the sites and to stimulate the production of both the combination of those two is phenomenal but it also is that they are absorbed.

So it's really working on both sides of the story and I think thats.

A powerful effect, it's not true for whom the other biologics and we looked at all of them, including Denosumab and pulled out stopped the program.

I don't think the other molecules have anywhere near the biological potency that this one does so I'm pretty confident that it stands above the others at this point.

Okay and then just final question is shape of R&D for this year. So I know you.

Part of this year and should we.

B continuing to.

Increase from here and then like a floor as we go into next year or how should we think about.

I know you said you were commenting on starting a lot of studies. So just wanted to understand that the shape of R&D.

R&D spend.

Well, I think maybe Marty, you want to answer?

A lot going on and we're trying to manage and I think Marty can give you a sense of what R&D.

Yeah, Hi, Lisa it's Marty.

We don't talk about Opex in general and our net cash use.

And I gave some examples that we believe SG&A and particularly next SG&A next year in particular will go down as we transition our commercial efforts at Christina.

Casey.

But R&D, we're funding our development programs right. So we have seven clinical trials, so that will continue to.

Continues to be a major part of our spend going forward, having said that.

We're very conscious of what we're spending and we have a lot of levers among the various programs. So we're measured and paced where we need to be we're still moving through major milestones.

Okay. Thank you.

Yes.

Thank you.

Our next question comes from Joseph Schwartz of <unk> Securities. Your line is open.

Thank you for Joe. Thank you for taking our question I have a question on E checks.

Our with anybody getting more data in the patients who just from coordinated when you provide your next update I'm, assuming are going to keep increasing the dose in these patients in the maintenance space, but I wanted to confirm that.

And would it be possible to adjust the schedule to see if they could benefit more on a more frequent dosing regimen in EMEA.

Thank you.

Yes, so when we provide our next update we will provide more data on the current patients and longer term data. They are tight trading until we hit where we think we need to hit on dosing and when we look at the broad program as we hit a dose where we think were right near the dose.

<unk> built into the protocol the ability to make an extra dose on a monthly scale for anyone in the three month period. So we can give an extra dose or two in order to top them up let's say to get to the right level. So that we do have that ability then rather than.

Load the more we just simply need to give one or two extra doses and that will we think would get them.

Optimized if we once we figure out what we think the right dose should be.

So we have a way forward to get more data on the current said make sure they're contributing fully and we're dosing them optimally.

Okay. Thank you very much.

Thank you. Our next question comes from you got Joshua Mitts.

Of Citi. Your line is open.

How should mubarak on for Yigal. Thanks for taking my questions. I guess, just a couple of commercial questions. It looks like your second quarter or should it yourselves.

A nice bump over last quarter, so, but if im looking at this correctly it seems like to hit the midpoint of your guidance you may be expecting.

Honestly decelerating quarterly growth during the second half. So we're just curious as to why you think that might be and how conservative your guidance might be and any commercial dynamics, there and then some.

Question on Brazil, It seems like the midpoint of your guidance.

You will need to see some growth or some accelerating growth in the second half. So our questions. What do you think the key drivers of that acceleration will be thanks.

Great.

We did see a big bump, which is kind of equal out a little bit of the lumpiness that we see I don't know.

Perhaps Eric do you want to say something about our guidance, but let's put it this way we put guidance because its our best estimate we think theres going forward and we certainly aren't going to then kind of caveat the guidance based on other parameters, but.

Any thoughts on <unk>.

Going forward for Chris Vita indulge lb.

Yes for both products is pretty much. The same we are expecting strong sales at the second half of the year.

Which has been the case if you look at the previous year's four four Chris leader.

So we're confident in our ability to.

Continue to grow.

Accelerated growth as we continue to find new patients and those patients get converted.

To treatment.

So we've generally had a stronger second half than first half is what youre, saying.

So.

That's our expectation for both products.

Yeah.

Okay got it thanks for the clarity and then maybe more of a conceptual question.

On your gene therapy pipeline I think you are up to.

Six distinct gene therapy programs and also I'm, just curious about how you're thinking about prioritizing between all.

All of these programs both from a development standpoint, but also from a spend standpoint, given your earlier comments about matching cash burn overtime.

Well, we've already been doing some of that staging because we've put the.

401 program <unk>, a kind of in the lead position or top priority program for them often get mold.

48 week study it had very strong data has very high demand and desire and with one we thought we could push forward more quickly OTC, we we staged a little bit further back to take the burn off it's going to take a little bit more time Wilson with somewhere between <unk> hundred 11 program. We've just added as an.

Actually.

Has treated all the patients we believe would be required in order to file. It's a question now of when the file so in that program. We're managing manufacturing this required and we might or how we should have some product and then she to treat additional patients but.

The program is a little bit more of like a post phase III program in spend wise and we will manage the commercial manufacturing part of it is the only piece that we really need to absolutely focus on.

And so that's how we're kind of working the ones. We have the earlier stage ones are our year back, but I agree we have a lot we.

We need to stage it manage it and our hope also is the gene therapy manufacturing plant will start picking up more of the load, especially on the earlier stage, one which will allow us to reduce our costs.

Our cost for clinical trials, and ultimately bring down our cost of goods as well for manufacturing improved.

Our consistency so with sophisticated products like this is necessary to invest in your own plan and that that's how we're going to continue to do.

To gain traction in our gene therapy program as being in control of the manufacturing as we move forward.

Okay, great. Thanks for answering my questions.

Thank you I'm showing no further questions at this time I'd like to turn the call back over to Joshua Hayward for any closing remarks. Thank you.

Thank you. This concludes today's call. If there are additional questions. Please contact us by phone or IR at <unk> Dot com. Thank you for joining us.

Thank you ladies and gentlemen, this does conclude today's conference. Thank you for participating you may now disconnect have a great day.

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I will comment a little bit more on the runway for you.

Good afternoon, and welcome to the Altra genetics second quarter financial results Conference call. At this time all participants are in a listen only mode. At the end of the program remarks, you will have the opportunity to ask a question during the Q&A portion of the call. It is now my pleasure to turn today's call over to Joshua Hager Executive director and head of Investor Relations.

Thank you.

We issued a press release detailing our financial results, which you can find on our website at <unk> Dot Com. Joining me on this call are <unk>, Chief Executive Officer, and President, Eric Harris, Chief Commercial Officer, Mardi Dier, Chief Financial Officer, and Camille Bedrosian, Chief Medical Officer, I'd like to remind everyone that during today's call we will.

Yeah.

We don't give specifics about when we'll be cash flow positive, but what we did say, just, to reiterate, that this is from the pathway towards profitability. And given our growth in revenues and our increased number of development programs moving forward, we do see our net cash use coming down, as I've said many times, but those development programs also give us a lot of flexibility and levers to pull if we need to manage our net cash firm moving forward and to get towards, you know, our ultimate goal would be to be cash flow positive and towards profitability.

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 I will now turn the call over to April .

Yes.

So, I don't know, Degas, if you want any more specifics.

Thanks, Josh and good afternoon, everyone.

We're now six months into the year and across the company will continue to make meaningful progress against our goals.

The commercial team delivered another solid quarter of revenue growth as they commercialize their products across the globe.

We acquired the late stage product <unk> 111 from <unk> for MPS, <unk>, or sanfilippo syndrome, and MTF disease area for which we have extensive experience.

We're not going to give a year's worth of data, but just to reiterate, we do see our, net cash use coming down, as I've said many times, but those development programs moving We're not going to give a year specifically, but importantly, we feel like we're in a good, cash position, prudence going forward, levers to pull to help manage the cash flow going forward, and increasing revenues. So, we feel like we're in a good position financially to move forward.

In July we bolster our cash position with a substantial royalty financing that also enabled us to acquire genetics and gained full control of our important Angelman program.

These activities along with progress across all of our early and late stage clinical programs put us in good strong position over the coming years for exceptional value creation.

Thanks, Joel.

Okay, great.

I want to touch on a couple of pipeline update before turning the call over to the other leadership team members to provide more detail on the quarter.

So plans for the cash are, well, we used a little bit already to acquire genetics, of, course, for the $75 million.

Thank you very much.

Okay.

Starting with Gtx 102 for Angelman syndrome, we reached a seminal moment in this program with the acquisition of genetics.

But I should balance that, and I think I said this in our script as well, is that we have, a lot of prudence in employing a lot of discipline in how we spend it.

So we're managing our headcount growth and slowing the rate of growth there.

And I should say, net cash use, just to reiterate once again, this is a peak year for a number, of one-time expenses, acquisitions, and in-licensing, and the start of a number of programs, et cetera.

We look forward that the net cash use will continue to decrease over time.

So, it puts us in good shape, Joel, moving forward.

And now have full control over the Gtx 102 program.

As we said on our call last week, we are all in on Angelman syndrome.

With the exceptional science regarding the target region and with the excellent data we've seen to date in phase one two study.

It's rare to see a significant improvement and development function as we have seen recently.

This is something I haven't seen.

In 30 years of drug development.

Last week, we shared data that demonstrate our ability to safely dose patients with gtx, one to add up to 10 milligram doses.

We observed meaningful clinical changes in a group of children that are severely impacted by the disease due to the deletion of the maternal Ub three gene region.

This severe mutation always predicts a very slow rate of learning on natural history as Dr. Byrd Kravets one of the principal investigators on the study said on our call last week.

These early clinical response across multiple domains and multiple clinical measures have been independently confirmed by clinicians therapist and patient families.

We observed statistically significant improvements for some of these children and expect to further enhance these effects by increasing loading doses and providing more time in the study.

One specific measure I would like to highlight is the bayley scales into development Bailey I'd like to remind you the bally's a standardized measure used to diagnose vulnerable delay in childhood.

It is administered in the clinic by trained therapists not the investigator and.

<unk> is often used in clinical trials to assess cognitive language and motor development in children.

In this study we're using the latest version of Bally, which allows for evaluation of children with delays, who exceed the bally age limit of neuro typical children.

The extensive historical data with this measure it allows the ability to assess statistical significance threshold for approval when evaluating individual patient results and showing theyre different from.

Air or variation, we know from natural history and the scores. This measure do not meaningfully change for patients with Angelman syndrome, particularly those with deletion type mutation.

Receptive and expressive communications hub scores that are important part of daily, particularly for patients with Angelman syndrome, who lack communication skills.

Cross the patient in cohort four and five and treated for a minimum of 128 days.

709 children showed a statistically significant improvement in either Bally receptive.

Operator, it seems like we might have lost <unk> audio connection can you confirm if are still out there.

One moment.

<unk> is still connected.

Yes.

I am here, Josh Okay loud and clear go ahead, Amy will continue alright.

Receptive communications important part of the daily, particularly for patients with Angelman syndrome, who lack communication skills.

Across the patients in cohort four and five and treated for a minimum of 128 days seven of nine children.

Sure a statistically significant improvement in either bally receptive or expressive communication score as of their most recent evaluation.

This compares favorably to two three of the original five patients who were treated in the U S who have statistically significant changes in the same score at day 128.

Our results from the original five patients also included patient reported results that were well past. The day 120 time point since many patients. We're four months passed their last dose at the time of that data release.

So the overall results of this objective third party measure combined with the Bally findings from natural history studies gives us confidence that we are improving communication skills in <unk> syndrome in a meaningful manner.

The full potential improvements of Bally communication measures will likely depend on the following patients for a longer period of time and starting with higher doses.

Okay.

In fact, all three of the ex U S patients to reach the day 170 evaluation in the current steady improved in both receptive and expressive communication beyond their day 128 results before receiving their first maintenance dose.

We have also amended the protocol in the UK and Canada and have begun dosing patients in additional dose selection cohorts with two patients dosed at the higher 755 dosing starting doses for the loading phase that we've already used to treat patients in cohort four and five.

One other important step forward the first patient from the originally treated U S. Cohort was readout last week in Canada with no reported drug related safety event.

Our team is also now working to found interim clinical study report with the FDA to support discussions that would allow for a harmonization of the U S and ex U S protocols.

With all of these components come together. This is the right point I'll check the lead development of this program.

We have the right expertise and capability to ensure a robust clinical program and regulatory strategy for <unk> 102.

Okay.

Great, thank you.

Thank you.

The history of development of Gtx, one two of the inspiring story for our team.

Thank you.

Our next question comes from Tazeen, Ahmad of Bank of America, your line is open.

It's a story of a group of parents, who defied the odds and their relentless pursuit of the right science and search for the right partner I firmly believe the right site was discovered and Scott didn't as lab and we now have an opportunity to bring one first Eric treatments to the interim and community.

Our next question comes from Dagon Ha of Stiefel.

Your line is open.

In the second quarter, we also announced the agreement to take on U S 111 in AAV gene therapy for the treatment of <unk> or sanfilippo syndrome.

NPS disease and gene therapy, they are very familiar territory for us.

And we believe that we can make a meaningful difference where the sampling of our community.

In the past and we work closely with the FDA to establish the use of alternative trial designs and endpoints to achieve approval and we believe the <unk> hundred 11 data are strong and support the use of the <unk> approval pathway.

Our team is hard at work on the filing strategy for a discussion with the agency and we look forward to providing updates later in the year.

With that I'll turn it turn it over to the team to provide updates on their function.

Great.

Thank you for taking my questions.

Thank you Emma and good afternoon, everyone I will start my section discussing our team's continued success commercializing crisp leader before shifting to the jewelry.

For Chris feeder within the profit share territory, we continue to find adult new adult and pediatric patients more than four years since launching the product.

As of the end of the second quarter over 2600 patients have been prescribed Chris meter and more than half are adults.

In the U S. We have penetrated almost 40% of the pediatric market and approximately 15% of the adult market.

Recall, finding pediatric patients similar to many other rare diseases, where the treatment is consolidated into centers of excellence.

This contrast to the finding.

Adult patients who are off were mostly being treated by community based physicians scattered across the country.

Our team is leveraging a mix of traditional in person meetings, along with innovative and interactive virtual programs to educate healthcare providers and patients as well as enhancing our digital online education presence.

We believe there is meaningful opportunity to steadily grow. The proceed of franchise with new identified patients as well as continued strong adherence within existing patients even four plus years into launch.

We will continue our efforts as we look towards transitioning the commercial responsibilities outside of the medical geneticist to key our Kieran and April 2023.

Outside of the profit share territory, primarily in Latin America. We are now seeing the results of our early launch efforts.

Second quarter revenue grew 32% versus the first quarter 2022.

And then the first half of the year, we have already surpassed the total revenue generated in this region last year.

In Latin America. There are there are over 250 patients on reimbursed therapy.

This will continue to grow as we continue expanding in Brazil, and as we gain momentum from our recent launches in Colombia and Mexico.

In Argentina, we continue to support named patient requests and look forward to gaining regulatory approval over the coming quarters.

Across all of the ultra <unk> regions, Chris reader revenue in the first half of 2022 grew 37% compared to the first half of 2021.

Based on our performance to date, we are reaffirming our 2022 revenue guidance and ultrasonics territories of $250 million to $260 million.

Good afternoon.

Mine are on Angel Men's.

Turning now to the Joey and beginning with our efforts in the U S. We continue to see steady growth across all of the leading indicators as a result of broad use in key metabolic genetic clinics across the U S.

Thanks for taking our questions.

Two from us.

One on 102, Emil, when the commentary or, I guess, guidance for the next update is contingent, upon substantial data, I guess, given that it's more of an individualized dosing on a per patient basis, can you maybe walk us through what that substantial data definition would be also because longer term duration of follow up seems to, I guess, correlate with better functional improvements?

One of the more promising statistics is that approximately 90% of all cases are approved for reimbursement in less than 30 days.

This isn't even faster turnaround time, and we saw for Christina.

At a similar stage of commercialization.

The team is also moving beyond the major centers for inborn errors of metabolism and is expanding the call coverage to other high potential health care professionals.

They are leveraging machine learning and artificial intelligence to generate new leads similar to what we are doing for Christina.

Outside of the U S use of the <unk> continues to add new physicians and patients through our named patient early access programs in Europe .

In Brazil, the health authorities approved the <unk> for the treatment of both pediatric and adult patients with LC <unk>.

Late last year.

We're continuing to work through the process to get full reimbursement approval, but this can take a little bit of time to complete.

At this point in the year, we are reaffirming the guidance of $55 million to $65 million that we put out in January .

I look forward to providing another update on this and other commercial programs next quarter.

And then second question for Marty, as we think about that, I guess, 1 billion plus, and the net cash burn seemingly coming down, I guess, can you maybe walk us through some of that sensitivity?

With that I'll turn the call over to Marty to share more details on the financial results for the quarter. Thanks.

Like, what kind of factors into, say, a cash runway of five years versus, say, till profitability?

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 June 32022 totaled $89 3 million Chris.

Thanks.

Sure.

I'll start, Marty, and you can deal with the cash questions.

Christy the revenue in <unk> territories was $64 million, including $51 6 million from the North American profit share territory, and net product sales of $12 4 million in other regions.

Total royalty revenue related to the sales of Chris Vita in the European territory with $5 4 billion.

<unk> revenue for the second quarter 2022 was $13 5 million.

<unk> revenue for the same period last $4 9 million.

Our total operating expenses for the second quarter 2020 to $230 9 million, which includes research and development expenses of 154, 5%.

SG&A expenses of $68, one and cost of sales of $8 3 million.

For the second quarter ended June 32022, net loss was $158 2 million or $2 26.

For sure.

During the first half of the year there have been a number of noncash items that have impacted net loss. This includes approximately 65 million of stock based compensation $20 million related decline in fair value of our equity investments and $13 million of noncash interest expense related to the royalty pharma.

Action. These are offset by approximately $10 million of noncash revenue also related to the royalty.

We ended the quarter with approximately 7 million $706 million in cash cash equivalents in marketable securities.

Subsequent to the ended the quarter in July we raised $500 million in non equity dilutive capital and then non dilutive non equity dilutive capital transaction with <unk> capital markets for the sale of a portion of our North America, Chris Bate a royalty.

Also exercised our option to acquire genetics and paid $75 million in July which allows us to take over the development of Gtx 102.

We are well capitalized with over $1 billion in the bank and we are making operating decisions to stage spend on our development programs and slowing head count growth in order to manage our burn as we have said 2022 with a peak burn year for us as we have initiated multiple late stage clinical programs.

In licensed <unk> completed the acquisition of genetics and are completing the build out of our gene therapy manufacturing facility.

In 2023, we don't anticipate additional one time events that this nature or large capital capital expenditures and we anticipate SG&A will decrease compared to 2022, as we transition U S and Canadian commercialization responsibilities for Kristina to K K C.

We will continue to invest in our clinical and preclinical programs as discussed and the overall net effect across the company then will be a decrease in net cash burn.

So, on what we're talking about in our next data output, I think we want to be clear that, we're not going to just release, you know, three or four patients worth of data at the next cohort as the next plan.

Now I'll turn the call over to Camille.

Thank you Marty and I too wish everyone. Good afternoon.

We'll be operating the dose escalation cohorts.

So Emil, when do you anticipate actually discussing with FDA about trying to, you know, align the protocol that you've got ex-US with the US?

This is truly an exciting time for clinical development at Alto <unk>.

We have seven programs in the clinic, including our ASO for Angelman syndrome that Emil discussed earlier.

On mrna for glycogen storage disease type III.

For late stage gene therapy trials, and the phase two three monoclonal antibody for Osteo <unk> and protector.

And as it relates to dosing, do you think that ultimately you may want to try to dose to where you had been dosing originally just at a slower titration?

And my section on today's call I will focus on this antibody you excellent four three or <unk>.

So do you think you could want to go to let's say 36 mix again?

We are developing for osteogenesis imperfecta.

Osteogenesis imperfecta Oi is caused by a defect in college in the <unk>.

And how long could that take if that's, you know, something that's on the table?

Thanks.

Else insignificant phone weakness and bone fragility, leading to factor it deformities stiffness and pain.

Yes.

Our plan on the US alignment was considered a top priority.

We have enough data now.

Currently there are no approved therapies for Oi.

So, that means we're in the game and we have an opportunity now to demonstrate the kind, of clinical results that we saw before and we're clearly seeing, as we've talked today quantitatively.

We think we just, we were asked to provide it in a CSR format, which we're doing, which requires a bit more effort.

As a company we have spent a lot of time studying bond biology, with XL H Tio and our preclinical candidate for Oi before we did the deal for <unk>.

We're doing that effort right now.

One of our key insight is that <unk> is not simply an issue of collagen is excessive bone resorption and the inadequate production of new bone triggered by this abnormal collagen that leads to low bone mass.

What we have found is that if you can increase bone formation and reversed the access of bone resorption, you can improve brown strength, even with the abnormal collagen.

And improved fracture prevention.

But the next time we want to talk about it, I want to make sure we have a substantial, amount of data that will provide confidence to all that we are in the right direction toward heading toward a phase three.

We'd hope to get that submitted and get the US patients going this year, because it would, certainly help us as we expand.

We believe this insight gives us the opportunity to change the future for patients with osteogenesis imperfecta them.

So that would be our goal to get them going this year, and to be part of that expansion.

Yeah.

That's our plan in the US.

I won't take time today to go back to all the details of the phase <unk> asteroid data that Mario has already presented.

I will comment a little bit more on the runway for you.

I do want to remind you of a few of the most important points.

This trial is a large randomized blinded study of 90 adult patients with Hawaii being studied across three different dose levels.

After 12 months the results indicated dose dependent and statistically significant effect on bone formation and bone mineral density.

Furthermore, the substantial bone mineral density improvement occurred across multiple.

Anatomical sites and the observed substantial bone formation, we believe is a very important factor in improving bone strength.

All of these findings were accompanied by a favorable safety profile.

Similar to how we develop roadmap for XL age when we took over developments from Kerala. Karen we are taking these impressive status and that results in adults with Hawaii and looking to further improve upon them for pediatric patients.

Currently we are enrolling and dosing patients with ally between the ages of five in 25 years with.

With the goal of using the CRM bone formation marker PD, one and <unk> to optimize the dose.

Once we have determined the pediatric dose strategy, we will transition directly into phase III evaluating the benefit is to choose an app on factor.

We don't give specifics about when we'll be cash flow positive. But what we did say, just to reiterate, that this is on the pathway towards profitability.

With this update I will now turn back the call to Emil Thank you.

I've had numerous conversations, and we are continuing to, to talk with the division in various ways and believe we can get that done.

And while we're having a little bit of a hard time I'm happy to finish this out.

I'm fine I just.

Problem with my phone, but I'm buying now thank you.

And given our growth in revenues and our increased number of development programs moving forward, we do see our net cash use coming down, as I've said many times. But those development programs also give us a lot of flexibility and levers to pull if, we need to manage our net cash for moving forward and to get towards our ultimate goal would be to be cash flow positive and towards profitability.

Now, with regard to the dosing, I don't think we need to go to 36.

You may all shipped in the Q&A portion of the call I'll provide a quick reminder of the key upcoming milestones.

So I don't know, Dagon, if you want any more specifics.

I think we already, remember that number originally was what happened was based on single dose data in the monkey to knock down.

We're not going to give a year specifically, but importantly, we feel like we're in a good, cash position, prudence going forward, levers to pull to help manage the cash flow going forward and increasing revenues. So we feel like we're in a good position financially to move forward.

Okay, great.

For U S $1 three an osteogenesis imperfecta will continue enrolling patients in the phase II portion of the study and expect to provide an update on the dose strategy for the phase III portion of around the end of the year.

Thank you very much.

Thank you.

Our next question comes from Tazeen, Ahmad of Bank of America.

Separately, we expect to initiate a study in children under five years old in the second half of the year.

Your line is open.

And our gene therapy pipeline with <unk> 111 for Sanfilippo, we're continuing to follow patients have been dosed in the pivotal study are continuing to evaluate the feasibility of filing for approval based on convincing biomarker data.

We will continue enrolling the phase III for <unk> hundred one and first stage of the <unk> 701 study.

We also expect to finalize startup activities for <unk> 301, and begin dosing patients later this year.

On the manufacturing side, we will continue to build out of our facility in Bedford, Massachusetts, which is on track to begin producing material in the first half of 2023.

For <unk> three in glycogen storage disease type III in the second half of the year, we expect to share single dose data from the first part of the phase one two study and to initiate the repeat dosing stage.

You can get to a single dose, but you don't need it.

For Gtx 102 in Angelman syndrome, we're also continuing to enroll cohorts six and seven at seven five or 10 milligrams outside the U S.

You can get to near maximum knockdown with giving the equivalent of, the equivalent of 10 milligrams three times.

Vacation is to provide the next update once we have determined an optimal dose and have gathered substantial data from the expansion cohort.

All of these programs create distinct opportunity to make meaningful difference for patients that are the reason we believe we have one of the most robust.

Diverse late stage pipelines in rare diseases.

Thank you for taking my questions.

So I honestly don't think it's necessary to get there.

With that let's move on to your questions. Operator, please provide the Q&A instructions.

Thank you, ladies and gentlemen, I would like to ask a question. Please press star one one when your touch tone telephone again, if you would like to ask a question. Please press star one line.

Mine are on Angel Men's.

I don't think we've loaded quite enough, yet.

But I also would say, if you look at the quantitative data we were just talking about in our deck, I think you'd see that actually from a quantitative data with the Bailey, we're actually at a very similar place to where we were.

So I don't think we're so far off.

I think getting into the 10 range is going to get us where we need to go once we give multiple doses of it.

One moment please.

So Emil, when do you anticipate actually discussing with FDA about trying to, you know, align the protocol that you've got ex-U.S. with the U.S.?

So I, right now I would not, I don't think that's necessary.

First question comes from Gena Wang of Barclays. Your line is open.

And as it relates to dosing, do you think that ultimately you may want to try to dose to where you had been dosing originally, just at a slower titration?

I think we can get there where we are and therefore just, we need to give it multiple times and we need to give it enough time to act, but I don't think going up to 36 is necessary.

So do you think you could want to go to, let's say, 36 mg again?

Okay.

Thanks Emil.

I have two quick questions first one is a Chris <unk> just wanted to make sure I heard correctly that you panic, just 15% adult market.

If that's the case I'm wondering how would you extend it out.

Our market share and how active you are to leverage family tree and the second question is regarding the Engelman program. Early this week updates wanted to note that.

<unk>.

Expansion cohort would that still be definition to clinical benefit will be to score in two domains and are you willing to open to dose higher than 14 milligram.

And how long could that take if that's, you know, something that's on the table?

And just to clarify about your discussions with FDA, will you need, do you feel like you'll need to have more confidence on what the final dosing regimen should be?

Thanks.

You know, collect all the information that you're collecting now before you go meet with FDA or does it not matter?

No, our feeling was we have enough data to enter the clinic and include U.S. patients in the dosing program that we're doing right now, that we can dose at the levels we're at, that we're doing it carefully and we can monitor and not seeing any, any drug related safety events.

Okay. Let me ask the second one first and then Eric you did touch on this christophene adult peds penetration question.

So the point is to get the U.S, involved in that dose determination phase, not afterwards.

So I don't think, I think their concerns were a number of questions about certain assays and things, or let's say certain biologies, which we've now shown are, do not occur.

And the fact that we've been able to dose safely with the new administration strategy, I think the number of elements of what we have should be sufficient to open the door to including the U.S. in the dose titration part of the study, as well as going forward.

So on the expansion.

So we're going to work to get that done as promptly as we can and get those patients in the U.S. in the program this year.

We're still using the two plus do you mean to set us create share for titration and we expect that we're going to be very close to where we need to be in fact.

Okay.

Great.

Going to be looking at all of our efficacy results, including the longer term results often tell us a little bit more about where we're at but we're that's what we expect.

Thank you.

Our next question comes from Corey Kozava of J.P. Morgan.

We don't expect to have to go beyond 14, frankly, I think we're very close so right now I wouldn't speculate on that I don't think I don't think its going be necessary. Once we start loading at this next cohort level, but we will want to make sure we do get the dose right and so we'll continue to evaluate what we're seeing both in the.

CGI score, but also on the quantitative scores and also over longer periods of time to make sure we're getting to a dose level that would provide us a substantial and meaningful clinical benefit that we could study in phase III.

Yes.

Our plan on the U.S. alignment with serotop priority, we have enough data now.

Now for the penetration I think we've been talking about the challenges of.

Finding adults were proceeded but the good part is when we find them when they do get prescribed.

So Eric maybe you can touch on the issue she's asking about with regard to penetration of the adult market, 15% versus piece, where it's much higher than.

What our expectations are what the challenges are.

Thanks, Jeremy Yes, you heard correctly penetration is 15% and the adult market versus 40% for the pediatric market.

No market represented represents about two thirds of the overall prevalence. So there is a significant growth opportunity with adults. It just takes longer to to pull through because as I stated many of these patients a loss in the system plus.

Accumulated physicians being treated for size of symptoms related to accelerate.

Not necessarily <unk>, excluding XL age, but one thing is any more to say that when we do find them, we're able to convert them at a very high rate and they stay on therapy.

We do offer genetic counseling.

Which which does pedigree.

Family Tree work and the work we've done to date, we think we are.

There are about two to four family members for each XL H program. So for each patient that's been identified they're about two to four on average that we're finding when patients take advantage of genetic counseling and family tree analysis.

So that is something that we will deleverage.

Thank you.

Our next question comes from Joel Beatty of Baird. Your line is open.

Your line is open.

We think we just, we were asked to provide it in a CSR format, which we're doing, which requires a bit more effort.

Thanks for the question.

We're doing that effort right now.

I was just wondering if you could provide any incremental color in the redosing of the, original five Angelman patients around their dosing paradigm, and will their data be included in the next readout?

Hi, Thanks for taking my questions.

Thanks.

With the new cash on hand from the recent deal what are your plans for this cash.

Well thank you.

Marty you want to answer sure yeah, yeah. Thanks, Joe So.

Yes.

I think it's a very important thing.

We've been pursuing this because those patients wanted to get redosed, so we wanted to give, them an avenue, given that we're unable to do that in the U.S. at this point in time.

We're able to get one good site for us in Canada to dose, and what they're doing is, they're dosing at the same cohort four, cohort five regimen, right, which is the 3.3 dose for the young patient, and it would be five dose for someone who's eight or older.

All right.

So it's going to be that same ladder of dosing that we used in cohort four and five.

For the cash are while we used a little bit already to acquire genetics of course with a $75 million that really the cash on hand, and now that we have over $1 billion of bank. We feel really good that this is going to fund our development program and really put us on this great pathway to profitability.

That's what they're going to get started with.

So the first patient has been dosed.

The second one is lined up.

We'll try to get as much as we can done that way until we hopefully get the U.S. open and, get the patients actually back in the U.S.

A little bit more refined we have some very in.

Meaningful milestones over the next few years and clearly the cash will get us through those.

Those milestones. It also allows us to maintain flexibility in terms of how and where we operate and so that should balance that and I think I said this in our script.

Script as well is that we have a lot of prudence and employing a lot of discipline in how we spend it so.

So we are managing our head count growth is slowing the rate of growth there and I should say.

But as we know, the first patient has been dosed safely, did well, did not have a problem, no drug-related safety issues, which is what we expected. There was no, like, reaction to the drug based on a history of exposure, which was what all, the biology said would be true.

So we're happy that it got started. I'm sad, though, that it's taken so long to get these kids back on, because they're just, aching to get back on, because all the stuff that was the benefit they saw before, they want to get back to it.

Net cash use.

Just reiterate once again.

This is a peak year for a number of one time expenses acquisitions and in licensing and the startup of a number of programs et cetera.

We look forward that the net cash use will.

Continue to decrease over time.

So we've got to get it to them as soon as we can.

So it puts us in good shape.

Moving forward.

Great. Thank you.

Thank you. Our next question comes from Dae Gon Ha of Stifel. Your line is open.

Great.

Thank you.

Our next question comes from Yarn Werber of Cowan.

Great. Good afternoon, thanks for taking our questions.

Your line is open.

Two from US one on one or two.

When the commentary or I guess guidance for the next update is contingent upon substantial data.

Given that it's more of an individualized dosing on a per patient basis can you maybe walk us through what that substantial data definition would be also because longer term.

Duration of follow up seems to.

Correlate with better functional improvements and then second question for Marty as we think about that I guess $1 billion, plus and the net cash burn steaming.

Seemingly coming down I guess can you maybe walk us through some of that sensitivity like what kind of factors into.

Our cash runway of five years versus say.

Tell profitability. Thanks.

Sure I'll start Marty you can deal with the cash question. So on okay. What we're talking about in our next data output I think we want to be clear that we're not going to just release.

I've got two quick ones, an Angelman and then one, actually, on 053.

Three or four patients worth of data at the next cohort as the next plan will be operating the dose escalation cohorts will then expand the cohorts and treat.

Our larger number of patients and what we said it will come out when we treat enough patients to give us a substantial efficacy result that we can speak to and that people can be confident in.

Rather than.

Small bits of data going forward, we think the mid year update was very important because it put forth to clarity that we can dose this drug and that you can do it without having drug related safety events and that we are seeing efficacy. So that means we're in the game and we have an opportunity now to demonstrate clinically meaningful results that we saw before.

Yes.

I will comment a little bit more on the runway for you.

No we don't give specifics about when we'll be cash flow positive.

We did say just to reiterate that this does put us on a pathway towards profitability.

And given our growth in revenues and our increase.

Number of <unk>.

<unk>.

Yes.

Moving forward, we do see our net cash is coming down as I've said many times, but those development programs also gave us a lot of flexibility and levers to pull if.

We need to.

Manage our net cash burn moving forward.

That's a lot of flexibility and levers to pull if.

We need to.

Manage our net cash burn forward and to get towards.

Ultimate goal would be to be cash flow positive and towards profitability.

So I don't know Doug if you want any more specifics, we're not going to give a year specifically, but importantly, we feel like we're in a good a good cash position.

Prudent going forward levers to pull to help manage the cash flow going forward and increasing revenues. So we feel like we're in a good good.

Position financially.

Alright.

Okay, great. Thank you very much.

Thank you. Our next question comes from <unk> of Bank of America. Your line is open.

Thank you for taking my questions.

So just on Angelman, I assume the FDA just wants to look at the clinical site reports, right?

Minor on Angelman.

So.

When do you anticipate Ashley discussing with SBA.

About trying to.

Align the protocol that you've got ex U S with the U S.

And as it relates to dosing do you.

Think that ultimately you may want to China's Jos to where you had been dosing originally just just at a slower titration. So.

Thank you want to go to lets say 36 months.

And how long could that tank.

Something thats on the table.

Yes.

Our plan on the U S alignment with Sarah top priority we have.

Have enough data now we think we just.

We were asked to provide it in the CSR format, which were doing which requires a bit more effort. We're doing that effort right now, which we would hope to get that submitted an <unk> patient is going this year because it would certainly help us as we expand so that would be our goal to get them going this year and to be part of that expansion.

We'd hope to get that submitted and get the U.S. patients going this year because it would certainly help us as we expand.

So that would be our goal, to get them going this year and to be part of that expansion.

That's our plan in the U.S.

So that's our plan in the U S. I've had numerous conversations and we are continuing to.

I've had numerous conversations and we are continuing to talk, with the division in various ways and believe we can get that done.

To talk with the division in various ways and.

Now, with regard to the dosing, I don't think we need to go to 36.

I believe we can get that done.

Now with regard to the dosing.

I don't think we need to go to 36, I think we already remember that number originally with what happened was based on single dose data and the monkey to knockdown you can get to a single dose, but you don't need it you can get to near maximum knockdown with giving the equivalent of.

I think we already, remember that number originally was what happened was based on single dose data in the monkey to knock down.

You can get to a single dose, but you don't need it.

You can get to near maximal knockdown with giving the equivalent of, the equivalent of 10 mg three times.

The equivalent of 10 milligrams three times so.

So I honestly don't think it's necessary to get there.

I honestly don't think it's necessary to get there.

I don't think we've loaded quite enough yet, but I also would say if you looked at the quantitative data we were just talking about in our deck.

I don't think we've loaded quite enough yet, but I also would say if you look at the quantitative data we were just talking about in our deck, I think you'd see that actually from a quantitative data with the Bailey, we're actually at a very similar place to where we were.

You'd see it actually from a quantitative data with the Bally were actually at a very similar place where we were so I don't think were so far off I think getting into the 10 range, it's going to get us where we need to go once we give multiple doses of it.

So I don't think we're so far off.

I think getting into the 10 range is going to get us where we need to go once we give multiple doses of it.

So I, right now I would not, I don't think that's necessary.

So right now I would not I don't think thats necessary I think we can get there where we are and therefore, just we need to give it multiple times and we need to give enough time to act, but I don't think going up to 36 necessary.

I think we can get there where we are and therefore just, we need to give it multiple times and we need to give enough time to act, but I don't think going up to 36 is necessary.

Okay.

Okay. Thanks, Raimo and just to clarify about your discussions with FDA will you need do you feel like you'll need to have more confidence on what the final dosing regimen should be collectively information that you are collecting now before you go meet with FDA or does it not matter.

Thanks, Emil.

No. Our feeling was we have enough data to enter the clinic and include U S patients in the dosing program that we're doing right now that we can dose levels. We're at but we're doing it carefully you can monitor and not seeing any any drug related safety events. So the point is to get the U S involved in that dose determination.

And just to clarify about your discussions with FDA, will you need, do you feel like you'll, need to have more confidence on what the final dosing regimen should be?

You know, collect all the information that you're collecting now before you go meet with FDA or does it not matter?

<unk> saved not afterwards, so I don't think I think their concerns were a number of questions about certain assays and things are let's say certain.

Myology, which we've now shown are do not occur.

And the fact that we've been able to dose safely with the new administration strategy.

No, our feeling was we have enough data to enter the clinic and include you as patients in the dosing program that we're doing right now, that we can dose at the levels we're at, that we're doing it carefully and we can monitor and not seeing any, any drug related safety events.

So the point is to get the U.S. involved in that dose determination phase, not afterwards.

So I don't think, I think their concerns were a number of questions about certain assays and things, or let's say certain biologies, which we've now shown are, do not occur.

In the program this year.

Okay, great. Thank you.

Okay.

Thank you. Our next question comes from Cory <unk> of Jpmorgan. Your line is open.

So we're going to work to get that done as promptly as we can and get those patients in the U.S. in the program this year.

Okay.

Great.

Alright.

Thanks for my question I was just wondering if you could provide any incremental color on the re dosing of the original five angelman patients.

Thank you.

Around their dosing paradigm.

Well their data be included in the next readout. Thanks.

Our next question comes from Corey Kozava of JP Morgan.

Your line is open.

Thanks for the question.

Yes, so I think it's a very important thing we've been pursuing this because those patients wanted to get re dose. So we.

I was just wondering if you could provide, any incremental color in the redosing of the original five Angelman patients around their dosing paradigm, and will their data be included in the next readout?

We wanted to give them an avenue given them, we're unable to do that in the U S. At this point in time.

We were able to get one good site for us in Canada to dose and what they're doing is they're dosing at the same cohort for cohort five.

Regimen, right, which is three three dose for the young patients and it would be five dose for someone who is eight or older alright. So its going to be that that same ladder of dosing that we used in cohort four and five that's what they're going to get started with.

Thanks.

So the first patient has been dosed the second one and signed up.

Reaction to the drug based on our history of exposure, So which was what all the biology set would be true. So we're happy that got started.

Yes, I think it's a very important thing.

We've been pursuing this because those patients, wanted to get redosed.

Does it has taken so long to get these kids back on because they are just a keen to get back on because all the stuff that was the benefit they saw before.

So we wanted to give them an avenue, given that we're unable to do that in the US at this point in time.

Want to get back to it so we've got to get to them soon as we can.

Great. Thank you.

We're able to get one good site for us in Canada to dose.

Thank you. Our next question comes from Yaron Werber of Cowen Your line is open.

And what they're doing is they're dosing, at the same cohort four, cohort five regimen, right?

Which is the 3.3 dose for the young patient, and it would be five dose for someone who's eight or older.

Sure.

Two quick ones and then some and then one <unk>.

All right, so it's gonna be that same ladder, of dosing that we used in cohort four and five.

Zero 53, so just an angelman.

I assume the FDA just wanted to look at the clinical site reports right theyre not necessarily waiting for.

So they're not necessarily waiting for Liz Barikravitz to have that natural history from, the four controls.

Elizabeth aircrafts to have natural history from the for controls.

And then secondly, if you do, if you're considering, obviously, doing an MDI as an endpoint, also, as opposed to, let's say, CSI-AS, once you choose the dose, is there a plan to then expand the study and maybe have a placebo, just to kind of have some experience with that before going to phase three?

And then secondly, if you do.

If you are considering obviously doing in MDI as an endpoint also as opposed to let's just see if I add.

Once you choose the dose is there a plan to expand the study that maybe have a placebo just to kind of have some experience with that before going into phase III and then I have actually a question separately on 53.

And then I have, actually, a question separately on 053.

Okay.

The controls were not really part of the safety story. They were part of assessing efficacy.

The patrol for not really part of the safety story, there a part of assessing efficacy.

And those controls have gone through their day 120.

Those controls have gone through their day 120, we just didn't have that data.

We just didn't have that data at the time of the release before.

At the time of the.

The release before so we can include that information, but I think the more important information was that the dosing administration safety in detail in our CSR.

So we can't include that information.

But I think the more important information was the dosing administration safety in detail, in a CSR, complete clinical study report format, GCP-compliant, REG-compliant format.

<unk>.

Local study report format GTP compliant Reg compliant format. That's what we were at four so we will be doing that on the <unk> data and will provide the U S data and update but I think that the <unk> is more important in this state.

That's what they're gonna get started with.

That's what we were asked for.

So the first patient has been dosed.

So we'll be doing that on the XUS data, and we'll provide the U.S. data and updates.

The second one is lined up.

We'll try to get as much as we can done that way, until we hopefully get the US open and get the patients actually back in the US.

But I think it's the XUS data that's more important in this state, and the control information will be in there.

With regard to the MDRI, the MDRI is the Multi-Domain Responder Index. It will look at multiple domains.

And the control information will be in there.

With regard to the MRI <unk> multi domain responder index will look at multiple domains, we will analyze the data we have by the method.

We'll analyze the data we have, by the method as we get there, but the expansion we're planning to do once we hit our dose will help us get a little more insight into the dose and how good it is and how have we really optimized it for all types and maybe provide us more color on the youngest patients versus the oldest patients and how the dose banding should be really conducted for a trial.

As we get there but.

The expansion, we're planning to do once we hit our dose will help us get a little more insight into the dose and how good it is and how have we really optimize it for all types of maybe.

Providing more color on that.

The youngest patients versus the oldest patients and how the the dose banding should be really conducted for a trial.

But as we know, the first patient has been dosed safely, did well, did not have a problem, no drug-related safety issues.

With regard to adding a control group, I guess there's a lot of interest now in what's the, magnitude of change.

So, which is what we expected.

With regard to adding a control group.

There was no reaction to the drug, based on a history of exposure.

So, which was what all the biology said would be true.

So we're happy that got started.

I guess theres a lot of interest now and what's the magnitude of changes seem to be the athene.

I'm sad though that it's taken so long, to get these kids back on because they're just aching to get back on because all the stuff that was, the benefit they saw before, they just didn't wanna get back to it.

It seems to be a theme.

So we gotta get to them as soon as we can.

I'm not sure why there's so much interest in it.

Great, thank you.

Thank you.

I'm not sure why there is so much interest in it.

I think we could add that kind of control group, but it does make things complicated.

We could add that kind of control group, but it does make things complicated I think the question of your own is whether you believe the amount of data or the size. The magnitude of the effect. We will have is incredible real effect or whether you're leaving those just placebo and I would say to you. The magna effect, where thing is clearly beyond placebo and were comfortable that it is.

I think the question of your own is whether you believe the amount of data or the size and, magnitude of the effect we will have is a credible real effect or whether you're believing that it's just placebo.

I would say to you the magnitude effect we're seeing is clearly beyond placebo and we're comfortable that it is.

As we get to the optimal dose, we'll have more data to say about what that effect is and its magnitude.

But as we get to the optimal dose your own will have more data to say about what that effect is of this magnitude.

Our hope would be that it would be clear.

And our hope to be there will be clear.

If a control group would help, we can look and think about that.

Right now, I think we're looking, for hopefully an incontrovertible large effect, which is where we're on track to do.

Right.

Right, Yeah, I guess look if it's a two point difference at 24 weeks I mean, it's one thing if it's <unk> nine or one one im just making numbers up random numbers obviously.

I guess if it's a two-point difference at 24 weeks, it's one thing.

If it's 0.9 or, a 1.1, I'm just making numbers up, random numbers, obviously.

It's obviously a little bit of a different discussion.

It's obviously a little bit of a different discussion I'll also not just for us obviously for regulators more importantly.

Also, not just for us, obviously, for regulators, more importantly.

Yes.

Yes, and then for you in terms of have you been power new endpoint for pivotal.

For you, in terms of how do you, empower a new endpoint for Pivotal?

While I'm jumping in, it looks like your phone might have clicked off again.

And while I'm jumping in it looks like your thought might've clicked off again.

Yes.

Yes, Unfortunately, my phone when it goes on whatever.

Sleep screensaver motive it basically turns off it appears so.

Unfortunately, my phone, when it goes on whatever sleep screensaver mode, it basically, turns off, it appears.

Sorry for that so.

So.

In any case I don't know when you'll ask me, but.

I don't think I think we should be seeing.

Sorry for that.

We should be seeing substantial data that would make us confident that it's not placebo and I actually think things were seeing already are.

Rarely see I've seen I've run the Bally and all kinds of blinded placebo open label trial.

Never seen things move beyond the variability of the test before we're seeing movements. There are significant beyond just the variation of the test already and I think that just is not something you see normally so I'm confident we're well past that and I think the quantitative data or actually a little more meaningful because they are an absolute.

Rather than a feeling.

Feeling about how they are changing so.

We're excited about what we're seeing your own I don't think we will need a placebo to make the call for phase III, but I understand the question, which is how confident will we be that what we're seeing is a real effect that will stand withstand the placebo controlled trial in Europe sensors, having some control might actually help us making that call, but I appreciate that.

<unk>.

Yes, because I mean.

If you look at the average data, which you know well really.

Less than a point of the year so.

In any case, I don't know when you lost me.

I think we should be seeing substantial data that would make us confident that it's not, placebo.

I actually think things we're seeing already are you rarely see.

And then maybe you can just a quick question I apologize for all these questions on marathon zero 53, four for GSD III, you're dosing IV Q2 weeks or so.

I've run the Bailey and all kinds of blinded, placebo, open-label trials.

I've never seen things move beyond the variability of the test before.

I'm confident we're well past that.

We're seeing movements that are significant beyond just the variation of the test already.

I think that just is not something you see normally.

Is there a chance to think about going sub Q and then secondly, just given whats the tolerability, so far and I know, it's very early given that it's an mrna therapeutics. Thank you.

It's very early I don't want to go into the details yes. It's very early in the program bar expectation is more likely to go once a month dosing not not every two weeks out of the limit edge of this thing our plan is to be once a month, we think once a month will be enough because in this case, we need to clear the abnormal.

Dexter and limit dextran storage material once you clear it doesn't accumulate that fast as you can clear it.

Even it doesn't matter if the drug is faded away after two or three weeks you still will be okay for a couple of weeks and then conclude again that makes sense.

Don't have to be completely clear continuously to get the benefit of the drug. So we're looking for monthly and we wouldn't necessarily go to sub Q, but certainly it hasnt done sub Q before.

Great. Thank you so much alright.

Our next question comes from Yarn Werber of Cowan.

I think the quantitative data are actually a little more meaningful because they're an absolute change rather than a feeling about how they're changing.

Thank you. Our next question comes from <unk> Richter.

Your line is open.

We're excited about what we're seeing, Yaron.

Goldman Sachs. Your line is open.

I don't think we'll need a placebo to make the, call for phase three, but I understand the question, which is how confident will we be that what we're seeing is a real effect that will withstand a placebo-controlled trial.

In your senses, having some control might actually help us making that call.

I appreciate that point.

I got two quick ones, an Angelman and then one, and actually a 053.

So just an Angelman, I assume the FDA just wants to look at the clinical site reports, right?

They're not necessarily waiting for Liz Berra-Kravitz, to have that natural history from the four controls.

<unk> develops naturally like more quick at a younger age versus when they are older and secondly about.

And then secondly, if you do, if you're considering obviously doing an MDI as an endpoint also, as opposed to let's say CSI-AS, once you choose the dose, is there a plan to then expand the study and maybe have a placebo just to kind of have some experience with that before going to phase three?

And then I have actually a question separately on 053.

The phase III study.

Do you have any guidance on when this might begin would you wait for the differentiator fees to align under the same protocol or could you see a.

Okay.

The controls were not really part of the safety story.

They were part of assessing efficacy, and those controls have gone through their day 120.

We just didn't have that data, at the time of the release before.

So we can include that information, but I think the more important information was the dosing administration safety in detail in a CSR complete clinical study report format, GCP compliant, reg compliant format.

A similar design of the phase one two whereas the dosing protocol is different from geography. Thanks.

That's what we were asked for.

So we'll be doing that on the XUS data, and we'll provide the US data and updates, but I think it's the XUS data that's more important in this state.

And the control information will be in there.

Yeah, because, I mean, the placebo, if you look at IVIG data, which you know well, really did less than a point in a year.

Sure.

So, in any event, maybe just a quick question.

First question I think it's pretty clear even from the first five original five patients currently now that the younger patient benefit.

I apologize for all these questions.

On 053, for GSD-3, you're dosing IVQ two weeks, so is there a chance to think about going sub-Q?

And then secondly, just given what's the tolerability so far?

Thank you.

And I know it's very early, given it's an mRNA therapeutics.

It's very early.

I don't want to go into the details yet.

It's very early in the program.

Benefit more rapidly certainly that part is.

Clearly they definitely get better more quickly I think it's also a factor potentially of dosing that is theyre getting a dose that for them is higher than it was for the others. So in the <unk>.

But our expectation is more likely to go once a month in dosing, not every two weeks.

That is the limit edge of this thing.

Our plan is to be once a month. We think once a month will be enough, because in this case, we need to clear the abnormal, you know, limit dextrin storage material. Once you clear it, it doesn't accumulate that fast.

If you can clear it, you know, it even doesn't matter if the drug is faded away, you know, after two or three weeks, you still will be okay for a couple of weeks and then can clear it again.

Current cohort before you all look the best but the core of <unk> getting a doses.

I don't think Asia is going to stop us completely from getting good effects I think we're going to see it it may be in different domains, but I still think we're going to see good effect in all of them I think we just need to make sure. The dosing is optimized and not just flat I think it's going to have to be adjusted for age.

Now with regard to the phase III, our plan would be to get the U S involved in the phase two study and certainly would need a synchronized global phase III, we would not want to have a separate <unk>.

In the U S Phase III program I don't think Thats. The smart move we think we can get the U S. Onboard I think they're being conservative at the moment, but I think we can provide the information they require and get them onboard.

Get the patients going in phase II.

Ultimately phase III.

Thank you. Thank you our next question.

Does that make sense?

Our next.

<unk> comes from Maury Raycroft of Jefferies. Your line is open.

Okay.

And on for Maury.

Just to clarify how much time gap is needed to address the next group of expansion patients. After the first two patients had been dosed in course six or seven.

You don't have to be completely clear continuously to get the benefit of the drug.

Okay. So the way the profile work as the first two patients in each cohort I guess, there are two doses and we assessed where theyre going.

So, we're looking for monthly, and we wouldn't necessarily go to sub-Q, but certainly it has been done sub-Q before.

Great.

<unk>.

They are you should be titrated, they'll get titrated, then right away. The next cohort will begin while the first.

Six and seven are getting their second two doses. The next cohort will begin right away. So there's a little faster turnaround now in terms of dosing up.

Does that help.

Okay makes sense, Okay, and then a quick question on the Williston, how is the pace of enrollment and do you think you can get stale.

Stage, one data escalation of the states to pivotal by year end up more like an immediate uptick.

Yes.

As we've said before the <unk> in the 701 or both and program. The FDA required a staged enrollment which was separated by several weeks before between each patient.

We will provide an update when we can but.

We are out there we're moving forward so.

It will take a little bit more time before we see phase two data from 701.

Thank you so much.

Thank you.

Thank you. Our next question comes from Joon Lee of <unk>. Your line is open.

The updates regarding gtx, one to one or two.

State your comment that 10 milligram in preclinical models that you'd near complete knocked out of the antisense, but do you have any evidence that it's actually leading to a meaningful ub create expression.

Correct me, if I'm wrong, but I'm not aware of any <unk> expression data in animal models. That's been publicly disclosed. Thank you. Yes June it does induce either we wouldn't be talking them out of it didn't.

It reduced <unk> expression, and particularly for us because our secrets homologous monkeys. So we can get a direct result of the monkey.

Unlike other situations so.

Because we are direct result, we also have turned out there is a single nucleotide polymorphism and <unk> in monkeys, which will help us in some manner from individual monkeys.

To distinguish between the <unk> coming from the return of the versus the paternal chromosome. So in those animals. We can look for the SNP in the paternal expression of the gene right and that allows us to determine that we're getting paternal expression in the monkey and we have in fact verified Ub Greg.

Depression.

At that dose level.

Can you quantify can you put that at a more quantifiable.

Context.

Well what happens when you get that expression you end up getting autoregulation, so you'll end up getting.

Very similar levels between mature.

Alright, so thorough at 50 50.

Okay, great. Thank you.

All right.

Thank you. Our next question comes from Lisa <unk> of Evercore ISI. Your line is open.

Thank you.

Our next question comes from Salveen Richter of Goldman Sachs.

Hi, Thanks for taking my question.

Just on the Angelman MRI.

Understand or was it wasn't totally tracking with the bally's versus CGI and why that's so.

So much more convincing and kind of like at the cycling out the noise can you maybe just speak to that again.

Well the CGI proven scale is a relative scale, where docs is minimal plus one plus two plus three is it's very sensitive because they're trying to compare before to after straight up and usually the quantitative the harder to move because they require a therapist to ask and do conduct.

Specific things that the Kid has to do in order to score right in order to move them forward.

So when you're trying to look across investigators in the study I think looking at the quantitative kind of gives you an objective how much was different right.

Okay.

And then.

With the Bally's, if it's kind of that as you said and more quantitative as the I'm just trying to think of as the kids are just like naturally did they.

I am sure. They are acquiring scale is just at a lower rate does that how does that factor into your thinking on sort of the background rate of change.

On the Bailey.

Sorry, ammo youre on mute again.

Alright.

My phone went off.

Alright.

Yeah.

Yes, so the Bally it's been studied in the natural history. It doesn't change I don't know coming up you have anything to say about the bally, but I thought it was not a member of natural history programs and not changing none the development really changes in the severe pain.

Yes, that's correct. Thank you Emil. Thank you also Alicia for the question.

The daily in particular communication is quite.

Flat over time.

Particular in individuals with deletion mutations.

And those are the patients who are studying at this time there are.

A number of references that illustrate T relative flatness of improvement.

And in these measures and we actually have one of those references sited.

In our.

Corporate deck.

And we're happy to follow up with you also on that.

Okay. Thank you and then just to now takes us into phase III. So I think you're thinking about the multi domain.

With regard to the MDRI, the MDRI is the Multi-Domain Responder Index, and we'll look at multiple, domains.

We'll analyze the data we have by the method as we get there, but the expansion we're planning, to do once we hit our dose will help us get a little more insight into the dose and how good it is and how have we really optimized it for all types and maybe provide us more color on the youngest patients versus the oldest patients and how the dose banding should be really conducted for a trial.

Endpoint, so would there be some combination of bally and CGI and other things or how should we be thinking about that.

I'm, obviously mean respondents would you only quantitative measures like Bailey.

Like in ancient severity score for sleep.

Et cetera. So.

There'll be a quantitative test for each domain and we'll have to set a minimum amount of change in order to be considered clinically meaningful in order to do the multimedia responder type of approach.

The value of course is that there is some heterogeneity, we can capture benefit across multiple domains. It's a lot more powerful. This type of analysis is very type of analysis is really tenfold more powerful than other types.

For many of these complex multi domain disorders.

Okay and I have two more questions is that okay. They are relatively quick.

One is beginning questions on <unk>, and like where it kind of fits into the treatment paradigm given there is.

Some other kind of treatments that can be used can you maybe just.

Explain how you are thinking about the target product profile and kind of where would it fit in the context of.

And today.

Yes, I'll just do that.

Look I think there's a lot of.

<unk> resort.

That our phosphate raw related compounds that have an effect on resort option, but they don't improve bone production. Therefore, there aren't really proving bond strength of trying to reduce the amount of excess absorption.

In there five randomized studies only two of them were positive and the magnitude of effect was a 20% reduction in fracture. So it makes patients feel better but it doesn't solve their fracture problem really and so we think that there are a lot of room for improvement there with regard to other biologics that are may be looked at I think the truth of the matter where the insight.

With regard to adding a control group, I guess there's a lot of interest now in what's the, magnitude of change.

It seems to be a theme.

I'm not sure why there's so much interest in it.

I think we could add that kind of control group, but it does make things complicated.

Score Austin is really by far the best in terms of its phenotype of inducing bone cells to become bone producing cells.

I think the question of your own is whether you believe the amount of data or the size, and magnitude of the effect we will have is a credible real effect or whether you're believing that it's just placebo, and I would say to you the magnitude effect we're seeing is clearly beyond placebo, and we're comfortable that it is.

Glass to ask you to ask the sites and to stimulate the production of both the combination of those two is phenomenal but it also is that their absorptive. So it's really working on both sides of the story and I think thats a powerful effect, it's not true for some of the other biologics and we looked at all of them, including Denosumab has been pulled out stopped.

The program.

I don't think the other molecules have anywhere near the biological potency that this one does so I'm pretty confident that it stands above the others at this point.

Okay and then just final question is shape of R&D for this year. So I know you.

Part of this year and should we be continuing to.

The increase from here and then like slower as we go into next year, how should we think about.

I know you said you.

You were commenting on starting a lot of studies. So just wanted to understand that the shape of it.

We have a lot going on and we're trying to manage it and I think Marty can give you a sense of whats R&D.

Yeah, Hi, Lisa it's Marty.

We talk about Opex in general and our net cash use.

And I gave some examples that we believe SG&A and particularly next.

G&A next year in particular will go down as we transition our commercial efforts at Christina.

Hey, Casey.

But R&D, we're funding our development programs right. So we have seven clinical trials, so that will continue to.

Continue to be a major part of our spend going forward, having said that we are.

Very conscious of what we're spending and we have a lot of levers among the various programs.

Measured and paced, where we need to be we're still moving through major milestones.

Your line is open.

Okay. Thank you.

Okay.

Thank you.

Our next question comes from Joseph Schwartz of SBB Securities. Your line is open.

Okay.

Please go Joe. Thank you for taking our question I have a question on E checks one pill.

Or would they be getting more data in the patients you just reported when you provide your next update and I'm, assuming you're going to keep increasing the dose in these patients in the maintenance space, but I wanted to confirm that.

And would it be possible to adjust the schedule to see if they could benefit more on a more frequent dosing regimen.

As we get to the optimal dose, we'll have more data to say about what that effect is, and its magnitude, and our hope would be that it would be clear.

Thank you.

If a control group would help, we can look and think about that, but right now, I think, we're looking for, hopefully, a incontrovertible large effect, which is, I think, what we're on track to do.

Right.

Yeah.

I mean, I guess, look, if it's a two-point difference at 24 weeks, I mean, it's one thing.

Built into the protocol the ability to make an extra dose on a monthly scale for anyone in the three month period. So we can give an extra dose or two in order to top them up let's say to get to the right level. So that we do have that ability then rather than.

If it's 0.9 or a 1.1, I'm just making numbers up, random numbers, obviously, then it's obviously, a little bit of a different discussion.

Also, not just for us, obviously, for regulators, more importantly, and for you in terms of, how do you empower a new endpoint for Pivotal?

Load the more we just simply need to give one or two extra doses and that will we think would get them.

Optimize if we once we figure out what we think the right dose should be.

So we have a way forward to get more data on the current said make sure that theyre contributing fully and we're dosing them optimally.

Hey, while I'm jumping in, it looks like your phone might have clicked off again.

Okay. Thank you very much.

Yeah, unfortunately, my phone, when it goes on whatever sleep screen saver mode, it basically, turns off, it appears.

Hi, this is Tommy on for Salveen.

Thank you. Our next question comes from Yigal Chacha Mitch.

Of Citi. Your line is open.

So, sorry for that.

Thanks for taking our question.

We have two on Angelman.

So, the first is that it seems based on the interim update that the younger patients benefited more, and we're wondering how much of this do you think might be due to the drug needed to be given earlier so that patients would develop naturally, like, more quick at a younger age versus when they're older?

And secondly, about the Phase 3 study, do you have any guidance on when this might begin?

Partially mubarak on for Yigal. Thanks for taking my questions I guess, just a couple of commercial questions. It looks like your second quarter appreciate ourselves.

Would you wait for the different geographies to align under the same protocol, or could you see a similar design as in the Phase 1-2 where the dosing protocol is different from geography?

Thanks.

Sure.

Well, from the first question, I think it's pretty clear, even from the first five, original five patients currently now, that the younger patients benefit more rapidly, certainly. That part is clear.

They definitely get better more quickly. I think it's also a factor, potentially, of dosing. That is, they're getting a dose that, for them, is higher than it was for the others. So, in the current cohort, the 4-year-old really looks the best, whereas the 4-year-old is getting a dose that's relatively higher than the kid who's 7 years old, right, who's much bigger.

So, I do think it's just an indicator both of dosing.

It could be age and, you know, being earlier, but we've seen improvements, and even the 13-year-old showed some nice improvements.

A nice bump over last quarter, so, but if I'm looking at this correctly it seems like to hit the midpoint of your pursuit of guidance you may be expecting modestly decelerating quarterly growth during the second half. So we're just curious as to why you think that might be and how conservative your guidance might be and any commercial dynamics. There and then similar question on <unk>.

So, I don't think age is going to stop us completely from getting good effects.

I think we're going to see it.

It may be in different domains, but I do think we're going to see good effects in all of them.

I think we just need to make sure that dosing is optimized and not just flat.

I think it's going to have to be adjusted for age.

Now, with regard to the Phase 3, our plan would be to get the U.S. involved in the Phase 2 study.

We certainly would need a synchronized global Phase 3.

We would not want to have a separate ex-U.S., in-U.S.

Phase 3 program.

It seems like at the midpoint of your guidance.

You will need to see some growth or some accelerating growth in the second half. So our questions. What do you think that the key drivers of that acceleration will be thanks.

Great well, we did see a big bump, which is kind of an equal a little bit of the lumpiness that we see I don't know.

So, in any case, I don't know when you lost me, but I think we should be seeing substantial, data that would make us confident that it's not placebo.

I don't think that's a smart move.

And I actually think things we're seeing already are, you rarely see, I've run the Bailey in, all kinds of blinded, placebo, open-label trials.

We think we can get the U.S. on board.

I've never seen things move beyond the variability of the test before, right?

Eric do you want to say something about our guidance, but let's put it this way we put guidance because thats. Our best estimate we think theres going forward and we start lapping and then <unk>.

So, we're seeing movements that are significant beyond just the variation of the test already.

And I think that just is not something you see normally.

So, I'm confident we're well past that.

Caveat the guidance based on other parameters, but.

And I think the quantitative data are actually a little more meaningful because they're an, absolute change rather than a feeling about how they're changing.

I think they're being conservative at the moment, but I think we can provide the information they require and get them on board, and get the patients going in phase two and ultimately phase three.

Thank you.

Any thoughts on going.

I'll go to the next question.

Going forward for Chris Vita indulge lb.

Our next question comes from Maury Raycroft, Jefferies.

Yes for both products is pretty much the same we're expecting strong sales the second half of the year.

Your line is open.

Which has been the case if you look at the previous year's four four Chris feeder.

So we're confident in our ability to.

Continue to grow.

Accelerated growth as we continue to find new patients and those patients get converted.

So, we're excited about what we're seeing, Yaron.

To treatment.

So we've generally had a stronger second half than first half is what youre, saying.

I don't think we'll need a placebo to make the call for phase three, but I understand, the question, which is, how confident will we be that what we're seeing is a real effect that will withstand a placebo-controlled trial in your senses?

Having some control might actually help us making that call.

So.

That's our expectation for both products.

Yeah.

So, I appreciate that point.

Okay got it thanks for the clarity and then maybe more of a conceptual question.

Yeah, because I mean, the placebo, if you look at IVIG data, which you know well, really did less than a point in a year or so.

Our gene therapy pipeline I think you are up to.

Six distinct gene therapy programs and also I'm, just curious about how you're thinking about prioritizing between all.

All of these programs both from a development standpoint, but also from a spend standpoint, given your earlier comments about matching cash burn overtime.

In any event, maybe just a quick question.

Yes, well, we've already been doing some of that staging because we put the <unk>. The 401 program <unk>, one a kind of in the lead position what top priority program for them often get mold.

I apologize for all these questions.

On 053, for GSD3, you're dosing IVQ two weeks.

So is there a chance to think about going sub-Q?

And then secondly, just given what's the tolerability so far?

<unk> 48 week study it had very strong data has very high demand and desire and with one we thought we could push forward more quickly OTC, we we staged a little bit further back to take the burn off it's going to take a little bit more time Wilson somewhere in between USD 111 program. We've just added as an.

And I know it's very early, given it's an mRNA therapeutics.

Thank you.

It's very early.

I don't want to go into the details yet.

It's very early in the program.

But our expectation is more likely to go once a month in dosing, not every two weeks.

That is the limit edge of this thing.

Our plan is to be once a month. We think once a month will be enough, because in this case, we need to clear the abnormal, you know, limit dextran storage material. Once you clear it, it doesn't accumulate that fast.

If you can clear it, you know, it even doesn't matter if the drug is faded away, you know, after two or three weeks, you still will be OK for a couple of weeks and then can clear it again.

Actually.

<unk> has treated all the patients we believe would be required in order to file.

Does that make sense?

You don't have to be completely clear continuously to get the benefit of the drug.

A question now when the file so in that program, we're managing manufacturing this required and we might or how we should have some product and then she to treat additional patients but.

All right.

So we're looking for monthly and we wouldn't necessarily go to sub-Q, but certainly it hasn't done sub-Q before.

The program is a little bit more like a post phase III program in spend wise and we will manage the commercial manufacturing part of it is the only piece that we really need to absolutely focus on.

And so that's how we're kind of working the ones. We have the earlier stage ones are our year back, but I agree we have a lot we need to stage it manage it and our hope also is the gene therapy manufacturing plant will start picking up more of the load, especially on the earlier stage, one which will allow us to reduce our costs.

Reduce our cost for clinical trials.

Ultimately bring down our cost of goods as well for manufacturing and improved our consistency so with sophisticated products like this it's necessary to invest in your own plan and that that's how we're going to continue to gain.

The gain traction our gene therapy program as being in control of the manufacturing if we move forward.

Thank you so much.

All right.

Okay, great. Thanks for answering my questions.

Thank you I'm showing no further questions at this time I'd like to turn the call back over to Joshua Hager for any closing remarks. Thank you.

Moving on from Maury, just to clarify, how much time gap is needed to enroll the next group of expansion patients after the first two patients have been dosed in core six and seven?

Okay, so the way the protocol work is the first two patients in each cohort gets their two doses and we assess where they're going.

If they are, should be titrated, they'll get titrated, then right away the next cohort will begin while the first six and seven are getting their second two doses, the next cohort will begin right away.

So there's a little faster turnaround now in terms of dosing up.

Thank you.

Does that help?

Thank you. This concludes today's call. If there are additional questions. Please contact us by phone or IR at Ultra Genex Dot com. Thank you for joining us.

Our next question comes from Salveen Richter of Goldman Sachs.

Okay, makes sense.

And then a quick question on the Wilsons, how is the pace of enrollment?

And do you think you can get the stage one data and selection of the stage to be able to by year end or more like early or mid year up to next year?

Thank you.

Yeah, as we've said before, in the 701 or Wilson program, the FDA required a staged enrollment, which was separated by several weeks before between each patient.

Your line is open.

Thank you.

This concludes today's call.

Thank you ladies and gentlemen, this does conclude today's conference. Thank you for participating you may now disconnect have a great day.

So, there wouldn't be possible to get through all the enrollment in that timeframe and get there.

Hi, this is Tommy on for Salveen.

Thank you.

Our next question comes from June leave twist.

If there are additional questions, please contact us by phone or at ir at Ultragenyx.com.

Thank you for joining us.

The enrollment has begun and we are enrolling patients, but it would, it basically stretches out the time of the enrollment for the phase one part of the program significantly.

Thanks for taking our question.

Thank you, I'll go to the next question.

You may now disconnect.

Your line is open.

Thank you.

You may now disconnect.

So it won't have data on Wilson by year end.

We have two on Angelman.

Our next question comes from Maury Raycroft, Jeffries, your line is open.

Have a great day.

Yeah, thanks regarding 1 or 1 or 2.

Ladies and gentlemen, this does conclude today's conference.

Have a great day.

We'll provide an update when we can, but we are out there.

So the first is that it seems based on the interim update that the younger patients benefited more.

In on for Maury.

I appreciate your comment that 10 milligram and preclinical models get you near complete knock down of the anti anti sense.

Thank you all for participating.

We're moving forward.

And we're wondering how much of this do you think might be due to the drug needed to be given earlier, that patients would develop naturally, like more quick at a younger age versus when they're older?

Just to clarify, how much time gap is needed, to enroll the next group of expansion patients after the first two patients have been dosed in core six and seven? Okay, so the way the protocol work, is the first two patients in each cohort gets their two doses and we assess where they're going.

But do you have any evidence that it's actually leading to a meaningful UB 3 expression correct me if I'm wrong, but I'm not aware of any UB 3 expression data in animal models.

So, it will take a little bit more time before we see phase one to data from 701.

And secondly, about the Phase 3 study, do you have any guidance on when this might begin?

If they should be titrated, they'll get titrated, then right away the next cohort will begin while the first six and seven are getting their second two doses, the next cohort will begin right away. So there's a little faster turnaround now, in terms of dosing up.

That's been completely disclosed.

Would you wait for the different geographies to align under the same protocol?

Does that help?

Thank you.

Or could you see a similar design as in the Phase 1, 2 where the dosing protocol is different from geography?

Okay, makes sense.

Yes, June, it does induce other where we wouldn't be talking about if it didn't induce UB 3 expression, particularly for us, because our sequence homologous to monkey.

Thanks.

And then a quick question on the Wilson's, how is the pace of enrollment?

So we can get a direct result for monkey.

Sure.

And do you think you can get the stage one data, and selection of the stage two pivotal by year end or more like early or mid year up to next year?

Unlike other situations, so, because we can get a direct result.

Well, from the first question, I think it's pretty clear, even from the first five original five patients currently now that the younger patients benefit more rapidly. Certainly that's that part is clear.

Yeah, as we've said before, in the 701 or Wilson program, the FDA required a staged enrollment which was separated by several weeks between each patient.

We also, as it turned out, there is a single need site, Paul morphism and UB 3 and monkeys, which will help us.

They definitely get better more quickly.

So there wouldn't be possible to get through, all the enrollment in that timeframe and get there. The enrollment has begun and we are enrolling patients, but it basically stretches out the time of the enrollment for the phase one part of the program significantly.

Some some individual monkeys to distinguish between the UB 3 coming from the maternal versus the paternal chromosome. So, in those animals, we can look for the snip in the paternal expression of the gene.

I think it's also a factor of potential dosing that is they're getting a dose that for them is higher than it was for the other.

So it won't have data on Wilson by year end.

Right and that allows us to determine that we're getting paternal expression in the monkey and we have, in fact, verified UB 3 expression in at that dose level.

So in the current cohort, the four year old really looks the best, but the four year old is getting a dose that's relatively higher than the kid who's seven years old.

We'll provide an update when we can, but we are out there, we're moving forward.

Can you quantify, can you put that in a more quantifiable context?

Right.

So it will take a little bit more time, before we see phase one, two data from 701.

Well, what happens when you get that expression is you end up getting autoregulation, so you'll end up getting very similar levels between maternal.

Who's much bigger.

Thank you.

All right, so they're like 50-50.

So I do think it's just an indicator both of dosing.

Our next question comes from June Lee of Truist.

Yes, great, thank you.

It could be age and being earlier, but we've seen improvements in even the 13 year olds showed some nice improvements.

Your line is open.

Thank you.

So I don't think age is going to stop us completely from getting good effects.

Yeah, thanks.

Our next question comes from Liisa Bayko of Evercore ISI.

I think we're going to see it.

Regarding GTS 102, I appreciate your comment, that 10 milligram in preclinical models that you've near complete knockdown of the antisense, but do you have any evidence that it's actually leading to a meaningful UB3A expression?

Your line is open.

It may be in different domains, but I think we're going to see good effects in all of them.

Correct me if I'm wrong, but I'm not aware of any UB3A expression data in animal models that's been publicly disclosed.

Hi, thanks for taking the question.

I think we just need to make sure that dosing is optimized and not just flat.

Thank you.

Just on Angelman, Emil, I didn't completely understand or wasn't totally tracking with the Bayleys versus CGI, and why that's so much more convincing and kind of like deciphering out the noise.

I think it's going to have to be adjusted for age.

Yes, June, it does induce.

Can you maybe just speak to that again?

Now, with regard to the phase three, our plan would be to get the US involved in the phase two study and certainly would need a synchronized global phase three.

Other words, we wouldn't be talking about if it didn't.

Well, the CGI improvement scale is a Erolito scale where it says minimal plus one, plus two, plus three.

We would not want to have a separate in the US phase three program.

It induced UB3A expression, particularly for us, because our sequence homologous to monkeys, so we can get a direct result for monkey, unlike other situations.

It's very sensitive because they're trying to compare before to after, straight up.

I don't think that's a smart move.

So because we can get a direct result, we also, as it turned out, there is a single nucleotide polymorphism in UB3A in monkeys, which will help us in some individual monkeys to distinguish between the UB3A coming from the maternal versus the paternal chromosome. So in those animals, we can look for the SNP, in the paternal expression of the gene, right? And that allows us to determine that we're getting, paternal expression in the monkey.

And usually the quantitatives are harder to move because they require a therapist to ask, and conduct specific things that the kid has to do in order to score, right, in order to move the score.

We think we can get the US on board.

And we have, in fact, verified UB3A expression, at that dose level.

The quantitative tends to be more rigorous and a stronger measure of absolute change, whereas the other test can be somewhat dependent on the investigator and their view of what minimal is or what much is.

I think they're being conservative at the moment.

Can you quantify, can you put that in a more quantifiable context?

Okay.

But I think we can provide the information they require and get them on board, and get the patients going in phase two and ultimately phase three.

Well, what happens when you get that expression is you end up getting autoregulation.

Yeah, so when you're trying to look across investigators in the study, I think looking at the quantitative kind of gives you an objective how much was different, right?

So you'll end up getting very similar levels between maternal.

And that's why I think it's a little better.

All right, so they're like 50-50.

That's why we're showing this comparison of quantitative because we're trying to show, okay, with different investigators, the Bailey is the same test done the same way by different people, but it's still a therapist doing the test and, therefore, I think is a more comparable way of comparing sites.

Yes, great, thank you.

Okay.

Thank you.

And then with the Bailey's, if it's kind of that, as you said, more quantitative, I'm just trying to think as the kids are just like naturally, I mean, I'm sure they're acquiring skills just at a lower rate.

Our next question comes from Liisa Bayko of Evercore ISI.

How does that factor into your kind of thinking on sort of the background rate of change on the Bailey?

Your line is open.

Sorry, Emil, you're on mute again.

Hi, thanks for taking the question.

Sorry, my phone went off.

Just on Angelman, Emil, I didn't completely understand or wasn't totally tracking with the Bayleys versus CGI and why that's so much more convincing and kind of like deciphering out the noise.

No worries.

Can you maybe just speak to that again?

Yeah, so the Bailey's been studied in the natural history.

Well, the CGI improvement scale is a relative scale where it says minimal plus one, plus two, plus three.

It doesn't change.

It's very sensitive because they're trying to compare before to after, straight up.

I don't know, Camille, if you have anything to say about the Bailey, but I thought it was in a number of natural history programs and not changing.

And usually the quantitatives are harder to move because they require a therapist to ask and conduct specific things that the kid has to do in order to score, right, in order to move the score.

None of the development really changes in the severe cases.

Yeah, that's correct.

Okay.

Thank you, Emil.

Yeah.

Thank you also, Lisa, for the question.

So when you're trying to look across investigators in the study, I think looking at the quantitative kind of gives you an objective how much was different, right?

The Bailey, in particular, communication is quite flat over time, and in particular in individuals with the deletion mutations, and those are the patients we're studying at this time. There are a number of references that illustrate the relative flatness of improvement in these measures, corporate deck.

And that's why I think it's a little better.

And we're happy to follow up with you also on that.

That's why we're showing this comparison of quantitative because we're trying to show, okay, with different investigators, the Bayley is the same test done the same way by different people, but it's still a therapist doing the test and, therefore, I think is a more comparable way of comparing sites.

Okay, thank you.

Okay.

And then just to now take this into phase three.

And then with the Bailey's, if it's kind of that, as you said, more quantitative as the, I'm just trying to think as the kids are just like naturally do that.

So I think you were thinking, about the multi domain kind of endpoint.

I mean, I'm, I'm sure they're acquiring skills just at a lower rate.

So would it be some combination of Bailey and CGI and other things?

Does that how does that factor into your kind of thinking on sort of the background rate of change on the Bailey?

Or how should we thinking about that?

Sorry, Emil, you're on mute again.

Yeah, well, the multi-domain respondents would use only quantitative measures like Bailey.

Sorry, I, my phone went off.

So the Bailey receptive expressive could be a communication domain.

No worries.

And we'd look at those two and measure communication change.

The, yeah, so the Bailey's been studied in the natural history.

We could use Bailey for the gross motor change as well.

It doesn't change.

We could do a different measure for sleep, like an ancient severity score for sleep, etc.

I don't know, Camille, if you have anything to say about the Bailey, but I thought it was in a number of natural history programs and not changing.

So there'll be a quantitative test for each domain.

None of the development really changes in the severe cases.

And we'll have to set a minimum amount of change in order to be considered clinically meaningful, in order to do the multi mean responder type approach.

Yeah, that's correct.

The value that there is some heterogeneity, we can capture benefit across multiple domains, it's a lot more powerful.

Thank you, Emil.

This type of analysis is a very type analysis is really tenfold more powerful than other types.

Thank you also, Lisa, for the question.

For many of these complex multi domain disorders.

The Bailey, in particular, communication is quite flat over time. And in particular, in individuals with the deletion mutations, and those are the patients we're studying at this time, there are a number of references that illustrate the relative flatness of improvement in, in these measures. And we actually have one of those references cited at, in our.

Okay, and I have two more questions.

Corporate Deck.

Is that okay?

And we're happy to follow up with you also on that.

They're relatively quick.

Okay, thank you.

One is a beginning questions on Sirtuzumab and like where it kind of fits into the treatment, paradigm given there's, you know, some other, you know, kind of treatments that can be used.

And then just to now take this into phase three.

Can you maybe just explain how you're thinking about the target product profile and kind of, where would it fit in the context of treatment today?

So I think you were thinking about the multi-domain kind of endpoint.

Yeah, I'll just do that.

So would it be some combination of Bayley and CGI and other things?

I look, I think there's a lot of anti-resorptive, you know, that are bisphosphonates and related compounds that have an effect on resorption, but they don't improve bone production.

Or how should we be thinking about that?

Therefore, they're not really improving bone strength.

Yeah, well, the multi-domain respondents would use only quantitative measures like Bayley.

They're trying to reduce the amount of excess resorption.

So the Bayley receptive expressive could be a communication domain, and we'd look at those two and measure communication change.

In the five randomized studies, only two of them were positive and the magnitude of effect was a 20% reduction in fracture.

We could use Bayley for the gross motor change as well.

So, it makes patients feel better, but it doesn't solve their fracture problem really.

We could do a different measure for sleep, like an angel severity score for sleep, etc.

And so, we think that there's a lot of room for improvement there.

So there'll be a quantitative test for each domain.

With regard to other biologics that are maybe looked at, I think Sirtuzumab or the anti-sclerosin, is really by far the best in terms of its phenotype of inducing bone cells to become bone-producing cells, blast to osteocytes, and to stimulate the production of bone.

And we'll have to set a minimum amount of change in, order to be considered clinically meaningful in order to do the multi-domain responder type approach.

The combination of those two is phenomenal, but it also is anti-resorptive.

The value of that, of course, is that there is some heterogeneity.

So, it's really working on both sides of the story, and I think that's a powerful effect.

We can capture benefit across multiple domains. It's a lot more powerful.

It's not true for some of the other biologics, and we looked at all of them, and including Denosumab has been pulled out, stopped the program.

This type of analysis is, MDR-type analysis, is really tenfold more powerful than other types for many of these complex multi-domain disorders.

And I don't think the other molecules have anywhere near the biological potency that this one does.

Okay, and I have two more questions.

So, I'm pretty confident that it stands above the others at this point.

Is that okay?

Okay.

They're relatively quick.

And then this final question is, shape of R&D for this year?

One is, I've been getting questions on sirtuzumab and where it kind of fits into the treatment paradigm, given there's some other kind of treatments that can be used.

So, I know you reported this year.

Can you maybe just explain how you were thinking about the target product profile and kind of where it would fit in the context of treatment today?

Will it be continuing to increase from here and then like slower as we go into next year, or how should we think about?

Yeah, I'll just do that.

I know you said you were commenting on starting a lot of studies.

Look, I think that there's a lot of antiresorptives that are bisphosphonates and related compounds that have an effect on resorption, but they don't improve bone production.

I just wanted to understand the shape of R&D spend.

Therefore, they aren't really improving bone strength. They're trying to reduce the amount of excess resorption.

We have a lot going on, and we're trying to manage it, and I think Marty can give you a sense of what R&D...

It's blast to osteocytes and to stimulate the production of bone.

Hi Lisa, it's Marty.

The combination of those two is phenomenal, but it also is antiresorptive.

We talk about OPEX in general and our net cash use, and I gave some examples that we believe SG&A next year in particular will go down as we transition our commercial efforts of CRISPR to KKC, but R&D, we're funding our development programs, right?

So, it's really working on both sides of the story, and I think that's a powerful effect.

So we have seven clinical trials, so that will continue to continue to be a major part of our spend going forward.

It's not true for some of the other biologics.

Having said that, you know, we're very conscious of what we're spending and we have a lot of levers among the various programs.

We looked at all of them, including dinosumab.

So we are measured and paced where we need to be.

It's been pulled out, stopped the program.

We're still moving through major milestones.

And I don't think the other molecules have anywhere near the biological potency that this one does.

Yeah, thank you.

So, I'm pretty confident that it stands above the others at this point.

Thank you.

Okay, and then just final question is shape of R&D for this year.

Our next question comes from Joseph Schwartz of SVB Securities.

So, I know you reported this year.

Your line is open.

Will it be continuing to increase from here and then lower as we go into next year?

For Joe, thank you for taking our question.

Or how should we think about, I know you said you were commenting on starting a lot of studies.

I have a question on UTX-202.

I just wanted to understand the shape of R&D spend.

Are we going to be getting more data in the patients you just reported when you provide your next update?

We have a lot going on, and we're trying to manage it.

And I'm assuming you're going to keep increasing the dose in these patients in the maintenance phase, but I wanted to confirm that.

I think Marty can give you a sense of what R&D.

And would it be possible to adjust the schedule to see if they could benefit more on a more frequent dosing regimen in the maintenance phase?

Hi Lisa, it's Marty.

Thank you.

Yep, so when we provide our next update, we will provide more data on the current patients and longer term data.

So we have seven clinical trials, so that will continue to be a major part of our spend going forward.

They are titrating until we hit where we think we need to hit on dosing.

Having said that, we're very conscious of what we're spending, and we have a lot of levers among the various programs.

And when we, through looking at the broad program, as we hit a dose where we think we're right at near the dose, what we have built in the protocol is the ability to make an extra dose on a monthly scale for anyone in the 3-month period. So we can give an extra dose or 2 in order to top them up and, let's say, to get to the right level.

So we are measured and paced where we need to be.

So that we do have that ability, then rather than load them more, we just simply need to give 1 or 2 extra doses and that will, we think, would get them optimized if we, once we figure out what we think the right dose should be.

We're still moving through major milestones.

So we have ways forward to get more data on the current set and make sure that they're contributing fully and that we're dosing them optimally.

Okay, thank you.

Okay, thank you very much.

Thank you.

Our next question comes from Joseph Swartz of SVV Securities.

Our next question comes from Yigal Natachemitz of Citi.

Your line is open.

Thank you for taking our question.

Thank you, Yigal.

I have a question on UTX-202.

Thanks for taking my questions.

Are we going to be getting more data in the patients you just reported when you provide your next update?

I guess just a couple of commercial questions.

And I'm assuming you're going to keep increasing the dose in these patients in the maintenance phase, but I wanted to confirm that.

It looks like your second quarter of Crescida sales showed a nice bump over last quarter.

And would it be possible to adjust the schedule to see if they could benefit more on a more frequent dosing regimen in the maintenance phase?

But if I'm looking at this correctly, it seems like to hit the midpoint of your Crescida guidance, you may be expecting modestly decelerating quarterly growth during the second half.

Thank you.

So we're just curious as to why you think that might be and how conservative your guidance might be and any commercial dynamics there.

Yep, so when we provide our next update, we will provide more data on the current patients and longer-term data.

And then a similar question on to Jolvie.

They are titrating until we hit where we think we need to hit on dosing.

It seems like to hit the midpoint of your guidance, you'll need to see some growth or some accelerating growth in the second half.

So, we can give an extra dose or two in order to top them up and, let's say, to get to the right level.

So our question is, what do you think the key drivers of that acceleration will be?

So, we do have that ability.

Thanks.

And rather than load them more, we just simply need to give one or two extra doses, and that, we think, would get them optimized once we figure out what we think the right dose should be. So, we have ways forward to get more data on the current set and make sure that they're contributing fully and that we're dosing them optimally.

Great.

Okay, thank you very much.

Yeah, well, we did see a big bump, which is kind of equal a little bit of the lumpiness that we see.

Thank you.

I don't know.

Our next question comes from Yigal Natachemitz of Citi.

Perhaps, Eric, you want to say something about our guidance, but let's put it this way.

Your line is open.

We put guidance because it's our best estimate we think is going forward and we certainly aren't going to then caveat the guidance based on other parameters.

Ashik Mubarak, on for you, Yigal.

But, Eric, any thoughts on going forward for Crescida and Jolvie?

Thanks for taking my questions.

Yeah, for both products, it's pretty much the same.

I guess just a couple of commercial questions.

We're expecting strong sales the second half of the year, which has been the case if you, look at the previous years for CRISPR.

It looks like your second quarter Crescida sales showed a nice bump over last quarter.

So we're confident in our ability to continue to grow, accelerate growth as we continue, to find new patients and those patients get converted to treatment.

But if I'm looking at this correctly, it seems like to hit the midpoint of your Crescida guidance, you may be expecting modestly decelerating quarterly growth during the second half.

Yeah, so we've generally had a stronger second half than first half is what you're saying, Eric.

So, we're just curious as to why you think that might be and how conservative your guidance might be and any commercial dynamics there.

So that's our expectation for both products.

And then a similar question on to Jolvie.

Okay, got it.

It seems like to hit the midpoint of your guidance, you'll need to see some growth or some accelerating growth in the second half.

Thanks for the clarity.

So, our question is, what do you think the key drivers of that acceleration will be?

And then maybe more of a conceptual question on your gene therapy pipeline.

Thanks.

I think you're up to six distinct gene therapy programs now, so I'm just curious about how, you're thinking about prioritizing between all these programs, both from a development standpoint, but also from a spend standpoint, given your earlier comments about managing cash burn over time.

Great.

Yeah, well, we've already been doing some of that staging because we've put the 401, program, or GS-1A, kind of in the lead position, top priority program, top priority milestone getting enrolled.

Yeah, well, we did see a big bump, which is kind of equal a little bit of the lumpiness that we see.

It's a 48-week study.

I don't know.

It had very strong data.

Perhaps, Eric, you want to say something about our guidance, but let's put it this way.

It has very high demand and desire.

We put guidance because it's our best estimate we think is going forward, and we certainly aren't going to then caveat the guidance based on other parameters.

And it was one we thought we could push forward more quickly.

But, Eric, any thoughts on going forward for Crescida and Jolvie?

OTC, we've staged a little bit further back to take the burn off.

Yeah, so for both products, it's pretty much the same.

It's going to take a little bit more time.

We're expecting strong cells the second half of the year, which has been the case if you, look at the previous years for CRISPR-Vita.

Wilson is someone in between.

So we're confident in our ability to continue to grow, accelerate growth as we continue, to find new patients and those patients get converted to treatment.

The UX-111 program we've just added is actually, has treated all the patients we believe would, be required in order to file.

Yeah, so we've generally had a stronger second half than first half is what you're saying, Eric.

It's a question now of when to file.

So that's our expectation for both products.

So in that program, we're managing the manufacturing that's required, and we should have some product, eventually to treat additional patients.

Okay, got it.

But the program is a little bit more like a post-phase three program in spend-wise, and we'll manage the commercial manufacturing part of it is the only piece that we really need to absolutely focus on.

Thanks for the clarity.

And so that's how we're kind of working the ones we have.

And then maybe more of a conceptual question on your gene therapy pipeline.

The earlier stage ones are a year back, but I agree we have a lot.

We need to stage it, manage it, and our hope also is the gene therapy manufacturing plant, will start picking up more of the load, especially on the earlier stage ones, which will allow us to reduce our costs and reduce our costs for clinical trials, and ultimately bring down our cost of goods as well for manufacturing and improve our consistency.

Yeah, well, we've already been doing some of that staging because we've put the 401, program, or GS-1A, kind of in the lead position with top priority program, top priority milestone getting enrolled. It's a 48-week study.

So with sophisticated products like this, it's necessary to invest in your own plant, and that's how we're going to continue to gain traction in our gene therapy programs is being in control of manufacturing as we move forward.

It had very strong data.

Okay, great.

It has very high demand and desire.

Thanks for answering my questions.

With one, we thought we could push forward more quickly.

Thank you.

OTC, we've staged a little bit further back to take the burn off.

I'm showing no further questions at this time.

It's going to take a little bit more time.

I'm going to turn the call back over to Joshua Higla for any closing remarks.

Wilson is someone in between.

Thank you.

The UX-111 program we've just added is actually, has treated all the patients we believe would, be required in order to file.

It's a question now of when to file.

So in that program, we're managing the manufacturing that's required, and we should have some product, eventually to treat additional patients, but the program is a little bit more like a post-phase three program in spend-wise, and we'll manage the commercial manufacturing part of it is the only piece that we really need to absolutely focus on.

And so that's how we're kind of working the ones we have.

The earlier stage ones are a year back, but I agree we have a lot.

So with sophisticated products like this, it's necessary to invest in your own plan, and that's how we're going to continue to gain traction in our gene therapy programs is being in control of the manufacturing as we move forward.

Okay, great.

Thanks for answering my questions.

Thank you.

I'm showing no further questions at this time.

I'm going to turn the call back over to Joshua Higua for any closing remarks.

Thank you.

This concludes today's call.

If there are additional questions, please contact us by phone or at ir at Ultragenyx.com.

Thank you for joining us.

Thank you.

Ladies and gentlemen, this does conclude today's conference.

Thank you all for participating.

Q2 2022 Ultragenyx Pharmaceutical Inc Earnings Call

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