Q4 2021 Ultragenyx Pharmaceutical Inc Earnings Call

February 10, 2022

Good day, ladies and gentlemen.

Thank you for standing by and welcome to the fourth quarter 2021 financial results and corporate update conference call. At this time, all participants are in a listen only mode. After the speakers presentation, there will be a question and answer session to ask a question during the session you only press star one on your telephone. Please be advised that today's conference is being recorded if you require any further assistance, please press star than zero. I would now like to hand the conference over to your host today, Joshua. Higgis sir, please go ahead.

Thank you for standing by and welcome to the fourth quarter 2021 financial results and corporate update conference call. At this time all participants are in a listen only mode. After the speaker's presentation. There will be a question and answer session to ask a question. During the session you repressed star one on your telephone please be advised for today's conference is being recorded.

If you require any further assistance. Please press Star then zero I would now like to hand, the conference over to your host today Joshua Sir. Please go ahead.

Good afternoon and welcome to the Ultragenics Pharmaceutical Financial Results and Corporate Update Conference call for the fourth quarter and full year 2021. We've issued a press release detailing our financial results, which you can find on our website at Ultragenics.com. I am Joshua Higa, Senior Director of Investor Relations. Joining me on this call are Emil Kakas, Chief Executive Officer and President, Camille Bedrosian, Chief Medical Officer, Eric Harris, Chief Commercial Officer, and Marty Deer, Chief Financial Officer.

Good afternoon, and welcome to the Ultra Gen X Pharmaceuticals financial results and corporate update conference call for the fourth quarter and full year 2021, we've issued a press.

Press release detailing our financial results, which you can find on our website at <unk> Dot Com I'm Joshua <unk> Senior director of Investor Relations. Joining me on this call are <unk>, Chief Executive Officer, and President Camille Bedrosian, Chief Medical Officer, Eric Harris, Chief Commercial Officer, and Mardi Dier Chief Financial office.

I would like to remind investors that this call will include forward looking statements within the meaning of the safe harbor provisions of the private securities litigation Reform Act of 1995. Including, but not limited to the types of statements identified as forward looking in our annual quarterly and periodic reports filed with the SEC, which are all available in the investor section on our website.

Sir.

I would like to remind investors that this call will include forward looking statements within the meaning of the safe Harbor provisions of the private Securities Litigation Reform Act of 1095, including but not limited to the types of statements identified as forward looking in our annual quarterly and periodic reports filed with the SEC, which are all available in the invest.

Section on our website.

These forward looking statements represent our views only as of the time of this call and involve substantial risks and uncertainties, including many that are beyond our control. Please note that actual results could differ materially from those projected in any forward looking statement.

For further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward looking statements, as well as risks related to our business, see our periodic reports filed with the SEC. I'll now turn the call over to Amal.

For a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward looking statements as well as risks related to our business see our periodic reports filed with the SEC I'll now turn the call over to Haynesville.

Thanks, Josh and good afternoon, everyone. We've.

We've had an exciting start to the year. We concluded a strategic rare disease deal with Regeneron to license global commercial rights outside of the US for both Efkisa and the potential for a second rare disease therapy, Goridizumab.

We've had an exciting start to the year, we concluded a strategic rare disease deal with Regeneron to license global commercial rights outside of the U S for both <unk> and the potential for a second rare disease therapy courageous mab.

We also released with our partner genetics a clinical update on the age-win program showing positive clinical activity and no lower extremity weakness events observed.

We also released with our partner genetics, a clinical update on the Haynesville program showing positive clinical activity in lower extremity weakness events observed.

We finished 2021 in a strong financial position exceeding expectations of the performance of our commercial products. And finally, we've made good progress with our broad late-stage pipeline.

We finished 2021 in a strong financial position exceeding expectations with the performance of our commercial products.

Finally, we've made good progress with our broad late stage pipeline.

where we have initiated enrollment in three of four pivotal programs that will be ongoing this year.

Where we've initiate enrollment in three of four pivotal program that will be ongoing this year.

Along the way, and despite the challenges presented by the COVID pandemic, we also successfully completed manufacturing technology transfer to our partner, Daiichi Sankeo.

Along the way and despite the challenges presented by the Covid pandemic. We also successfully completed manufacturing technology transfer to our partner Daiichi Sankyo.

I'll let Eric, Marty, and Camille provide more details on these accomplishments later on this call.

I'll, let Eric Marty and Camille will provide more details on these accomplishments later on this call.

I do want to spend a few minutes to discuss the deal with Regeneron on the commercialization of Evkisa for the treatment of homozygous familial hypercholesterolemia, or HOFH, outside of the U.S.

I do want to spend a few minutes to discuss the deal with regeneron on the commercialization of chiesa.

Treatment of homozygous familial hypercholesterolemia or HOS eight outside of the U S.

The deal also includes our exclusive right to negotiate a separate XUS agreement for their investigational antibody for fibrodysplasia, ossificans, progressive or FOP.

The deal also includes our exclusive right to negotiate a separate ex U S agreement for their investigational antibody for fibro dysplasia, <unk> progress CEVA or FRP.

This deal establishes a strategic partnership with a leader in high quality antibody drug discovery and development. It also enables us to both scale and leverage our global commercial capabilities in commercial medical affairs and regulatory functions.

This deal establishes a strategic partnership with a leader in high quality antibody drug discovery and development.

It also enables us to both scale and leverage our commercial global commercial capabilities.

Commercial medical affairs and regulatory functions.

Epqis is a potent approved product with a novel treatment mechanism that strengthens our portfolio with another commercial stage, traditional biologic that targets the underlying cause of HOF-8.

<unk> is a potent approved product with a novel treatment mechanism strengthens our portfolio with another commercial stage traditional biologic that targets the underlying cause of the age of age.

This disease occurs when two copies of the familial hypercholesterolemia causing genes are inherited, one from each parent, resulting in very low or absent LDL receptors on the liver and lead to dangerously high levels of LDL-C.

Disease occurs with two copies of the familial hypercholesterolemia are causing genes are inherited one from each parent, resulting in very low or absent LDL receptors on the liver.

It leads to dangerously high levels of LDL C. A P.

Patients with HOH are at risk for premature atherosclerotic disease and severe cardiac then.

Patients with <unk> are at risk for premature atherosclerotic disease.

And severe cardiac events.

Despite all the studies and all the work that's been done in this disease over many years, true homozygous null patients still don't have a great treatment approved. And apheresis to remove lipid from the blood each single, every single week is very difficult to tolerate and very cumbersome.

Despite all of the studies and all the work that's done in this disease over many years.

<unk> homozygous meld patients still don't have a great treatment approved in April <unk> to remove lifted from the blood. Each single every single week is very difficult to tolerate and very cumbersome.

Epkisa targets and binds the ang PTL3, which is a protein that plays a broad role in cholesterol regulation in atherosclerosis.

As Keith had targets and binds to <unk> III, which is a protein that plays a broad role in cholesterol regulation in atherosclerosis.

in patients whose LDL receptors are not present to direct appropriate liver uptake, as KEAS instead enables an alternative pathway by which VLDLs are converted into VLDL remnants that are rapidly cleared by the liver through an alternative set of receptors.

In patients, whose LDL receptors are not present to direct appropriate liver uptake of Keith instead enables an alternative pathway by which VLDL are converted into VLDL remnants that are rapidly cleared by the liver through an alternative set of receptors.

Taking advantage of this novel mechanism significantly reduces the level of LDL cholesterol in these severe patients despite the lack of working LDL receptors.

Taking advantage of its novel mechanism are significantly reduces the level of LDL cholesterol in the severe patients. Despite the lack of working LDL receptors.

The clinical value of blocking ang PTL-3 supported by data showing that natural genetic mutations also protect patients from atherosclerotic disease and treating LDL receptor deficient mice with an ang PTL-3 blocker does reduce angios atherosclerosis.

The clinical value of blocking <unk> III supported by data showing that natural genetic mutations also protect patients from atherosclerotic disease, and treating LDL receptor deficient mice with an <unk> blocker does reduce it Andrew atherosclerosis.

In Regeneron's pivotal clinical program for Epikiesa, the drug demonstrated significant improvement over standard of care with consistent 49% reduction in LDL-C in a 24-week study in 65 patients with HOFH on top of all existing LDL-lowering treatments.

And regeneron pivotal clinical program for <unk> Keith of the drug demonstrated significant improvement over standard of care with consistent 49% reduction in LDL C and the 24 week study in 65 patients with HOS H on top of all existing LDL lowering treatments.

The study also showed that treatment reduced the LDL-C by 72 percent in the most severe patients with less than 2 percent of LDL receptor activity. And that triglycerides were also reduced by 50 percent across study participants.

The study also showed that treatment reduced the ldlc by 72%.

In the most severe patients with less than 2% of LDL receptor activity and triglycerides were also reduced by 50% across study participants.

FKESOS also has a good safety profile, has been well tolerated across all study populations.

Gives us also has a good safety profile has been well tolerated across all study population.

EVKISA is approved by the FDA and EMA for patients 12 and older. Regeneron is currently marking the treatment as EVKISA in the U.S. and we will lead its launch in commercialization in all other countries and regions including Europe , Latin America and Asia.

Keith is proved by the FDA and EMA for patients 12 and older. Regeneron is currently marketing the treatment is a key thing in the U S and we will lead its launch and commercialization of all other countries and regions, including Europe , Latin America and Asia.

We may also expand our collaboration with Dronon to include another antibody in phase Q3 development called FOP.

We may also expand our collaboration with <unk> to include another antibody in phase three development called <unk>.

That license can include the same commercial rights, excluding the U.S.

That license will include the same commercial rights, excluding the U S.

FOP is an ultra-rare devastating genetic ectopic bone disease that affects approximately 1400 patients in these territories.

<unk> is an ultra rare devastating genetic topic bone disease that affects approximately 40 to 100 patients in these territories.

In patients with FOP, abnormal bone formation occurs in soft tissue like muscles, leading to freezing of movement and difficulties in eating, walking, and breathing, and leads to premature death by patients in their 50s.

In patients with <unk> abnormal bone formation occurs in soft tissue like muscles, leading to freezing of movement and difficulties in eating walking and breathing and leads to premature death by patients and their fifties.

I met my first patient with FOP while training in Los Angeles and recently presented a keynote at the IFOPA meeting, so I'm familiar with this horrible disease. Seeing patients frozen in terrible positions waiting for someone to save them or to freeze completely is not a sight you readily forget.

I met my first patient with <unk> training in Los Angeles, and recently presented a keynote at the <unk> meeting so I'm familiar with this horrible disease seeing patients frozen and terrible positions waiting for someone to save them.

Or to freeze completely does not cite you readily forget.

I'll now hand the call over to Eric who will talk about the commercial team's performance last year and what is Teaming is doing to launch FKISA.

I'll now hand, the call over to Erik who will talk about the commercial team's performance last year and what is teaming is doing to launch <unk>.

Thank you Emil and good afternoon, everyone I.

I'll start my section discussing the commercialization team's performance in 2021, despite the impact of the Omicron variant.

I'll start my section discussing the commercialization teams performance in 2021, despite the impact of the home grown variable.

For Chris Vida within the North American Territory, we continue to see steady underlying demand from both the pediatric and adult market.

Well Kristina within the North American territory, we continued to see steady underlying demand from both the pediatric and adult markets in the fourth quarter. We added over 50 unique prescribers in the U S alone.

In the fourth quarter, we added over 50 unique prescribers in the US alone.

The split of pediatric and adult patients remains approximately 50-50.

The split of pediatric and adult patients remains approximately 50 50.

while the total number of patients on therapy continues to increase.

The total number of patients on therapy continues to increase.

We expect this split will continue shifting towards a greater portion of adults on Chris Data as the teams are increasingly finding doctors.

We expect this split will continue shifting towards a greater portion of adults. When Chris is the teams are increasingly finding doctors, who have adult patients with <unk> with tio in the community setting.

who have adult patients with XLH or TIO in the community setting.

The compliance rates remain high. In fact, four years into this launch, we continue to hear stories from patients about how much better they feel once they begin receiving therapy.

The compliance rates remain high in fact four years into this launch we continue to hear stories from patients about how much better they feel once they begin receiving therapy.

Outside of North America, the man for Chris Peter continues to gain momentum.

Outside of North America demand for <unk> continues to gain momentum.

<unk> 2021 product revenue grew one 7% to $21 $4 million, while there might be variability in the ordering patterns that cause some quarter to quarter fluctuations in revenue. It's clear we are a strong underlying demand for Christina.

This is a direct result of all the work the teams have been doing to educate providers.

find patients, and work with regulatory and reimbursement authorities.

Find patients and work with regulatory and reimbursement authorities.

For 2022, we expect per-suitor revenue in ultragenics territories to be between $250 and $260 million.

For 2022, we expect procedure revenue and ultra agenda ultra gimmicks territories to be between 250 and $260 million.

The midpoint of this range represents 32% year-over-year growth, an impressive metric four years into a rare disease long.

Point of this range represents 32% year over year growth, an impressive metric for years into a rare disease launch.

Turning now to the Jovi and starting with the US launch next.

Turning now to the jewelry and starting with the U S launch metrics in the fourth quarter 2021, we added approximately 40 start forms bringing the total since launch to approximately 350 start forms as of.

In the fourth quarter 2021, we added approximately 20 star forms, bringing the total since launch to approximately 350 star forms.

As of the end of the fourth quarter, this has led to approximately 280 patients on reimbursed fare.

The end of the fourth quarter. This has led to approximately 280 patients on reimbursed therapy Approx.

Approximately 160 unique healthcare providers have written a prescription for Dijove with many of them writing prescriptions for multiple patients.

Approximately 160 unique healthcare providers have written a prescription for <unk> with many of them writing prescriptions for multiple patients.

outside of the US, use of the Jovian continues.

Outside of the U S use of the <unk> continues.

through our main patient and early access programs. In Europe , the JOBY growth is driven by significant increases in main patient requests in France and Italy.

Through our main patient and early access programs in Europe . The Dolby growth was driven by significant increases in named patient requests in France and Italy.

We are continuing to work with regional authorities as we look to expand access for all patients who could benefit from the job.

We are continuing to work with regional authorities as we look to expand access for all patients who could benefit from digital.

late last year, the Brazilian National Health Surveillance Agency.

Late last year, the Brazilian National Health surveillance agency.

the jogging for the treatment of both pediatric and adult patients with LC-FAOD.

<unk> for the treatment of both pediatric and adult patients with LC <unk>.

The final step is to get full reimbursement approval from Brazil's Ministry of Finance, a process we have begun working through for the last few months.

The final step is to get full reimbursement approval from Brazil's Ministry of Finance a process. We are again working through for the last few months.

I should note this will be the last quarter that we.

that we provide specific launch metrics for the Jovian. We believe the 2022 guidance range of $55 to $65 million.

<unk> specific launch metrics would be joking.

We believe the 2022 guidance range of $55 million to $65 million.

better representation of the confidence we have in our ability to continue finding patients and getting them on reimbursed there.

Better representation of the confidence we have in our ability to continue finding patients.

Getting them on reimbursed therapy.

Now, shifting gears to the opportunity we have with EPC-TEASE.

Now shifting gears to the opportunity we have with Keith.

which is approved for the treatment of HOFH, an inborn error of metabolism like most of our portfolios.

Which is approved for the treatment of HOS AIDS, an inborn error of metabolism by most of our portfolio.

These patients are typically seen by cardiovascular but their structures may have aids N

These patients are typically seen by cardiovascular and lipid specialists.

HOFH is also a fairly well developed market with established diagnosis protocols, knowledgeable physicians, and a relatively high estimated rate of identified patients.

<unk> is also a fairly well developed market with established diagnosis protocols now.

Eligible physicians and our relatively high estimated rate of identified patients.

Across the ultragenics territories, we estimate there to be between 3,000 and 5,000 patients with HOFH.

Across the ultra generics territories, we estimate there to be between 3000 5000 patients with H O S. H.

This program will help further establish us as a truly global commercial organization.

Initially, commercialization efforts will focus on Europe , where we estimate there to be approximately 1600 pages.

Initially commercialization efforts will focus on Europe , where we estimate there to be approximately 16 hybrid patients as.

As we modestly build on the current infrastructure that is supporting MEPS-TEBI and DIGYOVI, we will also work to submit dossiers and begin reimbursement discussions.

As we modestly build on the current infrastructure that is supporting <unk>. We will also work to submit dossiers.

And again reimbursement discussions.

This team will also be in place to respond to requests for main patient action.

This team will also be in place to respond to requests for named patient access which could begin in 2022, given the strong interest we have seen from the Kols community.

which could begin in 2022, given the strong interest we have seen from the KOL community.

in Latin America and Canada, our commercial and medical affairs infrastructure is already well established and ready to add FPs into their portfolio.

And lastly, Latin America, and Canada are.

Our commercial and medical affairs infrastructure is already well established and ready to add ftes it to their portfolios.

We have in place today the field teams and patient and prescriber support services needed to successfully launch F-KESER with very little build-out required.

We have in place today, the field teams and patient and prescriber support services needed to successfully launch <unk> with very little Buildout required.

The addition of FQs into our portfolio also sets the stage for our long-term commercial efforts as we expand into the APAC region.

The addition of <unk> to our portfolio also sets the stage for our long term commercial efforts as we expand into the APAC region.

This is a new geography for ultragenics, where we recently established a Japanese entity and have hired a general manager.

This is a new geography for ultra agenda, where we recently established Japanese entity and have hired a winner.

<unk> management.

While F-KESER will help UltraGenics to advance along its mission of being a truly global rare disease company, we should note that each of these regions are unique and have complex pricing and reimbursement processes.

While that Keith will help ultrasonics to advance along its mission of being a truly global rare disease company.

We should note that being that each of these regions are unique and have complex pricing and reimbursement processes.

We have begun these efforts, but as you all know, it can take some time to work through these processes and see revenue from our new therapy.

We have begun these efforts, but as you all know it can take some time to work through these processes and see revenue from our new therapy.

Key opinion leader feedback on the program is very supportive, and the strong clinical data speak for themselves is a significant leap forward for patients with HLA.

Key opinion leader feedback on the program is very supportive.

And the strong clinical data speak for themselves as a significant leap forward for patients with HOS H.

My colleagues and I look forward to offering Epqeza a new and compelling treatment option for patients.

My colleagues and I look forward to offering.

The new and compelling treatment option for patients.

In closing, I would like to reiterate just how proud I am of the team's efforts in 2021. And I look forward to 2022. We will continue to build on that.

In closing I would like to reiterate just how proud I am of the team's efforts in 2021.

And as I look forward to 2022, we will continue to build on that momentum.

With that, I'll turn the call over to Marty to share the financial results.

With that I'll turn the call over to Marty to share the financial results.

Great. Thanks, Eric. We issued a press release earlier today that included a financial update, which I will briefly summarize. Company revenue for the 12 months ended December 31, 2021, totaled $350.4 million. CRISP-FEDA revenue in ultragenics territories grew to $192.6 million, including $171.2 million from the North America Profit Shared Territory and net product sales of $21.4 million in other regions.

Great. Thanks Derrick.

We issued a press release earlier today that included a financial update which I will briefly summarize.

Company revenue for the 12 months ended December 31, 2021 totaled $354 million.

This beat our revenue and ultra Gen X territory grew to $192 6 million, including $171 2 million from the North America profit share territory, and net product sales of 21 $4 million in other regions.

Total royalty revenue related to the sales of Chris Fida in the European territory was $18.2 million. The D

Total royalty revenue related to the sales of Christy that in the European territory with $18 2 million.

Dolby revenue for the year with $39 6 million as Eric mentioned, the ongoing strength of the line just reflected in our 2022 guidance for <unk>, which represents approximately 50% growth at the midpoint of the guidance range.

Next, WEE for 2021 was $16 million. As we have previously stated, we expect these revenues may modestly increase over time.

Yes, Debbie for 2021 with $16 million as we have previously previously stated we expect these revenues may modestly increase over time.

2021 revenues also included 85 million related to the tech transfer as part of our strategic manufacturing partnership with Aichi Senkyo around our PCL and HEC 293 gene therapy technology.

2021 revenues also included $85 million related to the tech transfer as part of our strategic manufacturing partnership with Daiichi Sankyo around our PCL and had 293 gene therapy technologies and.

In the fourth quarter, 2021, the technology transfer activities were substantially completed and total revenue recognized under this license agreement through December 31, 2021 is $174.2 million.

In the fourth quarter 2021, the technology transfer activities were substantially completed.

And total revenue recognized under this license agreement through December 31, 2021 is $174 2 million.

Our total operating expenses for the year were $733.1 million, which includes research and development expenses of $497.2 million, SG&A expenses of $220 million, and cost of sales of $16 million. I should note this also includes a one-time expense of $50 million related to the upfront payment for the Morayo license and collaboration agreement regarding the Truth of Math for OI.

Our total operating.

<unk> for the year were $733 1 million, which includes research and development expenses of 400, $497 2 million SG&A expenses of $220 million and cost of sales of $16 million.

Should note. This also includes a onetime expense of $50 million related to the upfront payment from our rail for the Marine our license and collaboration agreement regarding the Nab for ally.

We continue to expect our R&D spend to somewhat increase in 2022 as we support three pivotal gene therapy clinical studies, the UX 143 Phase 2-3 clinical study in Hawaii, the Angelman Phase 1-2 study, and the Phase 1-2 study for our most advanced mRNA programs, UX 053 and GSD3, and a number of other preclinical activities as we get ready to advance the next programs into the clinic.

We continue to expect our R&D spend is somewhat increase in 2022 as we support three pivotal gene therapy clinical studies <unk> III phase III clinical study in Hawaii. The Angelman phase one two study and the phase two study for our most advance mrna program <unk> <unk> and GST three.

And a number of other preclinical activities as we get ready to advance the next programs into the clinic.

We also expect SG&A to modestly increase in 2022 as we continue to support the expansion and launches of our existing commercial products and the launch of EPCISA.

We also expect SG&A to modestly increase in 2022, as we continue to support the expansion and launches of our existing commercial products and the launch of <unk>.

For the year ended December 31st, 2021, net loss was $454 million or $6.70 per share. The net loss includes a $42.1 million decrease in the fair value of equity investment.

For the year ended December 31, 2021, net loss was $454 million or $6.70 per share.

The net loss includes the $42 $1 million decrease in the fair value of equity investments.

Net cash used in operations for the 12-month end of December 31, 2021 was $338.7 million, compared to $132.2 million for the same period in 2020. Net cash used in the 12-month period end of December 31, 2021 included the $50 million upfront payment for the closing of the Morial Agreement.

Net cash used in operations for the 12 months ended December 31, 2021 was $338 7 million compared to $132 2 million for the same periods of 2020.

Net cash used in the 12 month period ended December 31, 2021 included the $50 million upfront payment for the closing of the morale agreement.

This compared to the net cash used in the same period of 2020 that included approximately $155 million of operating cash received from Daiichi Thankyou related to the collaboration and license agreement.

This compared to the net cash used in the same period of 2020 that included approximately $155 million of operating cash received from Daiichi sankyo related to collaboration and license agreement.

We ended the year with approximately $1 billion in cash, cash equivalents and marketable securities. This puts us in a strong position to achieve critical milestones and expand our commercial presence over the next few years.

We ended the year with approximately $1 billion in cash cash equivalence and marketable securities. This puts us in a strong position to achieve critical milestones and expand our commercial presence over the next 10 years.

Now I'll turn the call over to Camille to touch on some of our clinical programs.

Now I'll turn the call over to Camille can touch on some of our clinical programs.

Thank you, Marty, and I too wish everyone a good afternoon. In my section, I will briefly provide status updates on our six clinical stage programs before turning back the call to Emil. Starting with the three...

Thank you Marty and I too wish everyone. A good afternoon, and my section I will briefly provide status updates on our six clinical stage programs before turning back the call to AMOLED.

Starting with the three gene therapy programs.

DTX401 for the treatment of glycogen storage disease type 1A or GSD1A is currently dosing patients in the randomized placebo controlled phase 3 study.

<unk> hundred one for the treatment of glycogen storage disease type <unk> or <unk> is currently dosing patients in the randomized placebo controlled phase III study.

DTX301 for the treatment of ornithine transcarbamylase, or OTC, deficiency is in the final stage of the study startup. We anticipate the first patients will enter the four to eight week baseline screening period in the first half of 2022, after which they will be dosed in the phase three randomized placebo controlled study.

Gtx 301 for the treatment of ornithine <unk> or OTC deficiency is in the final stages of study start up.

We anticipate the first patients will enter the four to eight week baseline screening period and the first half of 2022, after which they will be dosed in the phase III randomized placebo controlled study.

UX701 for the treatment of Wilson disease is currently enrolling patients in a seamless phase 1, 2, 3 randomized placebo controlled study.

<unk> 701 for the treatment of Wilson disease.

Currently enrolling patients in our seamless phase 123 randomized placebo controlled study.

Outside of gene therapy, UX 143 or cetruzumab, an anti-scorostin antibody, will begin enrollment in the first half of 2022 and the seamless SAVES 2-3 study for pediatric and young adult patients with osteogenesis in perfect...

Outside of gene therapy.

<unk> three or <unk>, an anti <unk> antibody will begin enrollment in the first half of 2022 and the seamless phase III study for pediatric and young adult patients with osteogenesis imperfecta.

GTX 102, the ASO in development with our collaborator genetics for patients with Angelman syndrome, continues to enroll and dose patients under the amended phase 1-2 protocols in the UK, Canada and the US with no reported lower extremities.

Gtx, one or two the ASO in development with our collaborator genetics for patients with Angelman syndrome continues to enroll and dose patients under the amended phase II protocol and the UK, Canada and the U S with no reported lower extremity weakness.

Cohorts four and five in the UK and Canada following DSMB support have expanded, adding an additional A patient to this protocol.

Cohorts four and five in the U K and Canada. Following DSM be support have expanded adding an additional eight patients to this protocol.

The initial assessments have shown early signs of clinical activity.

The initial assessments has shown early signs of clinical activity.

We look forward to providing an update on this program in mid-2022.

We look forward to providing an update on this program in mid 2022.

UX053, our first mRNA for the treatment of glycogen storage disease type 3, is currently dosing patients in the single ascending dose arm of the phase 1-2 study.

<unk> <unk> three our first mrna for the treatment of glycogen storage disease type III is currently dosing patients in the single ascending dose arm of the phase one two study.

Preliminary data from that arm, as well as initiation of the repeat dosing phase of the study, are anticipated in the second half of this year.

Preliminary data from that arm as well as initiation of the repeat dosing phase of the study are anticipated in the second half of this year.

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

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

Thank you, Camille. Before we close out, I'll provide a quick reminder of the key upcoming milestones for the company.

Thank you Camille before we close out I'll provide a quick reminder of the key upcoming milestones for the company.

For GTX 1 and 2 and Angeman, we'll provide an update in mid-2022 on cohorts 4 and 5 in the Canada and UK arm of the study, as well as available safety and efficacy data from the patients treated in the US.

For Gtx, one or two in Angelman will provide an update in mid 2022 on cohorts four and five in Canada, and UK arm of the study as well as available safety and efficacy data from the patients treated in the U S.

For our gene therapy pipeline, we'll continue enrolling the three late-stage clinical programs and we'll look to provide longer-term durability data from the Phase 1-2 studies for GSD1A and OTC at major conferences.

For our gene therapy pipeline will continue enrolling the three late stage clinical program and we'll look to provide longer term durability data from the phase one two studies for <unk> and OTC at major conferences.

For UX 143 in Osteogenesis and Perfecta, we'll begin dosing in the pivotal phase 2-3 study in Pediatrics in the first half of the year.

For U S $143, two jensen perfect that will begin dosing in the pivotal phase III study in pediatrics in the first half of the year.

In the second half of the year, we expect to provide an update on the dose strategy we have selected for the phase 3 portion and initiate a supportive study in children under 5 years old.

In the second half of the year, we expect to provide an update on the dose strategy. We have selected for the phase III portion of initiate a supportive study in children under five years old.

For UX053 in the second half of the year, we expect to share single dose data from the first part of Phase I-II study and to initiate the repeat dosing stage.

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

In 2021, we made meaningful steps in building a strong financial position, bolting our commercial portfolio, advancing our clinical programs and completing the tech transfer our gene therapy manufacturing technology ahead of schedule. In 2022, we look forward to building on this and sharing updates with you.

In 2021, we made meaningful steps in building a strong financial position bolstering our commercial portfolio advancing our clinical programs and completing the tech transfer our gene therapy manufacturing technology or ahead of schedule in 2022, and we look forward to building on this and sharing updates with you.

With that, let's move on to your questions, operator. Please provide the Q&A.

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

Thank you. If you have a question at this time, please press star then 1 on your touch tone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. We ask that you please limit yourself to 1 question or 1 follow up. Our first question comes from the line of Yikio Nakamoto with City Group. Your line is open. Please go ahead.

Thank you if you have a question at this time. Please press Star then one on your Touchtone telephone. If your question has been answered very wish to remove yourself from the queue. Please press the pound key we ask that you. Please limit yourself to one question and one follow up.

Our first question comes from the line of <unk> <unk> with Citigroup. Your line is open. Please go ahead.

Great, thank you very much, Tig. No question. I just had a question with respect to your planning for the pivotal trial for Hingelman. Presumably, you're going to do a randomized placebo-controlled trial. And so my question is, assuming you see a mean CGIS increase in line with the 2 and 1 aspect you've observed so far in the phase 1,2

Great. Thank you very much for taking the question I just had a question with respect to your planning for the pivotal trial for Angelman, presumably youre going to do a randomized placebo controlled trial and so my question is assuming you see a mean CGI Inc.

Increased in line with the two and a half that you've observed so far in the phase one two.

How are you thinking about the separation from placebo given the natural history on Angelman's where clinicians have actually observed slow gains in function over time? For instance, there's a 2020 publication in the Journal of Autism and Developmental Disorders that makes this point quite nicely. Thanks.

Are you thinking about the separation from placebo, given the natural history and Angelman.

Clinicians have actually observed slow gains any function over time for instance, there is a 2020 publication in the journal of autism and developmental disorders that makes this point.

<unk> quite nicely. Thank you.

Thank you, Gail. I think one thing about angeman is though there may be some small gains over time, the gains are pretty modest compared to the kind of change observed in the trial. So I have no question if we can achieve the efficacy we've seen before in our phase 3.

Thank you Paul I think one thing about <unk> is though there may be some small gains over time the gains are pretty modest compared to the kind of change observed in the trial. So I have no question. If we can achieve the efficacy we've seen before in our phase III that we'll be able to distinguish that from placebo Im really no concern at all the CGI.

that we'll be able to distinguish that from placebo, really no concern at all. The CGI as a tool is one approach to measuring the disease, but it is a more subjective approach depending on the opinion of the investigator. We also are certainly going to use underlying...

As a tool as one approach to measuring disease, but it has a more subjective approach depending on the opinion of the investigator. We also are certainly going to use underlying instruments.

that we used before, such as Bailey's and others, that are specific measures of particular function, which we will be studying in our phase two study currently with genetics, which will allow us to understand the magnitude of effect and understand the separation. And I have no doubt, given the effect we've seen before, that we can design a study that will have appropriate endpoints and capture what was, in our view, a very profound effect on development in this disease.

We use before such as Bay leaves and others that are specific measures of particular function, which we will be studying in our phase. Two study currently with genetics, and which will allow us to understand the magnitude of effect and understand separation and I have no doubt given the fact, we've seen before that we can design a study that will have appropriate.

Endpoints and Meg and capture what was in our view a very profound effect on development in this disease right now we need to get our optimize our dosing, which we're working on and figure out. This we'll figure out the magnitude of these effects and come up with a design for the study, whether it's CGI dependent or whether it's based on other.

Right now we need to get our optimizer dosing, which we're working on and figure out this, we'll figure out the magnitude of these effects and come up with a design for the study. Whether it's CGI dependent or whether it's based on other endpoints, I would say we still have some time to figure that out, but I think your question or concern raised and we certainly will look carefully at ensuring we're powering and observing a change that's meaningful.

Endpoints I would say, we still have some time to figure that out involved but I think your question or concern raised and we certainly will work look carefully at assuring repowering and absorbing a change thats meaningful.

Okay, thank you. That's super helpful. And then just to follow up on another topic regarding the Regeneron deal, obviously this was very interesting. You usually see the smaller company license to the larger firm to commercialize an asset, but obviously the reverse happened here.

Okay. Thank you.

And then just to follow up on another topic regarding the regeneron deal.

Obviously this was very interesting as you usually see the smaller company license to the larger pharma to commercialize an asset, but obviously the reverse happened here. So the question is could we see more transactions following what happened with <unk>.

So the question is, could we see more transactions following what happened with EBCZA?

or was this more of a one-off situation that presented itself with Regeneron? Thanks. Yes, well I think we just are a big company in how we act and behave, so that's what's going on here. But Regeneron is a great company but they haven't built a global...

Or was this more of a one off situation presented itself will generate.

Yes, well I think we just are a big company and how we act and behave so that's what's going on here now, but regeneron is a great company, but they haven't built a global commercial capabilities, especially in the rare space.

capability, especially in the rare space. They were appreciative of what we had and felt the best thing for their product. And they really cared about these patients. They wanted to get good care. And they said, we want you guys to handle this product because they have confidence in our belief to take care of business and do it well. So if there's anything that's our reputation for taking care of people correctly that draw us together, it is a true problem.

We're appreciative of what we had in and felt the best thing for their product and they really care about these patients wanted to get good care and they said we want you guys to handle this product and we have confidence our belief to take care of business and do it well so theres anything as our reputation for taking care of people correctly correctly that draw together. It is a two product deal.

Look, we're pretty full of the fizzy and pipeline right now. So right now we're not expecting to do many deals on other commercial deals, but...

Look we are we're pretty full with busy in pipeline right now so right now we're not expecting to do.

Many deals on other commercial deals, but in our view, we want to be selective we want to pick products that we want to work on that we're proud of that we think really change care in our part and important.

In our view, we want to be selective. We want to pick products that we want to work on that we're proud of, that we think really change care and are important, in order to get us to take our precious people's time and put them on an effort. And with KISA, we think we'll be a change in standard of care. And we think Gorizmab has the potential to be life-changing for FOP. So we're excited about both of those. And right now, we'll stick to just keeping those going, and we won't think about what else could be.

In order to get us to take our precious people time and put them to on an effort in the pizza, we think as well.

We will be to change the standard of care and we think <unk> has the potential to be life changing for FRP. So we're excited about both of those and right now we'll stick to just keeping those going in we won't think about what else could be.

We'll wait and see if it comes.

Okay, appreciate it. Thank you.

Okay I appreciate it thank you.

Thank you and our next question comes from the line of Gina Wang with Barclay. Is your line is open? Please go ahead.

Thank you and our next question comes from the line of Gena Wang with Barclays. Your line is open. Please go ahead.

Thank you for taking my questions. I also have one question regarding endermen. So, I mean, in the early January update, you said, you know, the sign of improvement in terms of CGI score.

Thank you for taking my questions I also have one question regarding Ann Julian.

So emil.

The early generally update you said.

Sign of improvement in terms of the CGI score. So did you continue to see that trend if you can be.

So did you continue to see that trend? If you can be a little bit more quantified regarding the score improvement. In the past, you mentioned like two score improvement in two out of five domains. Did that meet that criteria? And then second part is mid this year, can you lay out specifically what kind of data are we expecting to see from the 12 patients? Like for example, the first two patients from each cohort, the loading dose after initial loading dose, what additional data we could see and also for the remaining eight patient, what we could see. And will you have a definitive answer by mid this year that you will know which dose to move forward for a pivotal study.

Be a little bit more quantify be gliding the score improvement in the past you mentioned like two score improvement in two out of five domains did that meet that criteria.

And then second part is mid this year can you lay out specifically what kind of data are we expecting to see from the 12 patient might for example, the first two patients from each cohort the loading dose after initial loading dose what additional data we could see and also for the remaining patients.

We could see and will you have a definitive answer by mid this year that you would know which dose to move forward.

Pivotal study.

Very good. So thank you Gina. For Angelman, what we said was, and we'll just reiterate

Okay. Good so thank you gena for Angelman.

What we said was and we will just reiterate that.

We had improvements in clinical activity, that is their CGI scores for the domains were improving. But in the lower dose cohort, we had said that they hadn't achieved plus two in more than two domains. Therefore, the patients escalated to the next dose level.

We had.

We had improvements in connectivity that is theyre CGI scores for the domains where improving.

But in the low dose cohort, we had said that they hadn't achieved plus two and more than two domains. Therefore, the patients escalate to the next dose level.

In cohort five, the older patients, that DMC has met and also allowed the expansion of to the cohort five, the additional four patients.

Cohort five the older patients that DMC has met and also allows the expansion of to the cohort five additional.

For patient in that cohort.

And those patients also escalated. That is, they were seeing improvements, but not two dillings, two plus. So we're at the beginning of the titration. We still wanted to get in the clinic, get started. We're seeing activity. We're not seeing any lower extremity issues right now. So we're encouraged. They'll continue to dose and titrate as we move forward with those 12 patients. So that's what we're looking for.

And those patients are also escalated that as they they were seeing improvements, but not to doing two plus so we're at the beginning of the titration. We wanted to get in the clinic started we're seeing activity, we're not seeing any lower extremity issues right. Now. So we're encourage they'll continue to dose and titrated as we move forward with those 12 patients. So.

kind of where we're at. We haven't put out specific scores, but we said if they had two domains of 2+, they wouldn't titrate further. That would be considered getting to the level of efficacy we saw before. So we're encouraged, but we're continuing to move forward with dosing and titration.

Kind of where we're at we Havent put out specific scores, but we said if they had two domains of two plus they wouldn't titrate further that would be considered getting to the level of efficacy. We saw before so we're encouraged but we're continuing to move forward with dosing and titration.

Now, what kind of data will we see? Well, we're talking about mid-year.

Now what kind of data will we see what we're talking about mid year.

that that data would be, expectation would be that we would see data from the first cohort four and cohort five that have gotten their doses and evaluated at day 128, which includes now a whole series of endpoints, not just CGIs and domains, but it would include the Bayley's expressive and language scores, violin scores, sleep evaluations, and as well as the...

That that data would be expectation would be that we would see data from the first cohort four and cohort five that had gotten their doses and evaluated.

De 128, which includes now a whole series of endpoints not just CGI and domain, but will include the bally's expressive and language scores Vineland scores fleet evaluations.

And as well as the.

was one of behavior evaluation. So we would have a number of endpoints that would be supporting. Those endpoints would come from both patients or families.

I was wondering behavior evaluation so.

We would have a number of endpoints that we'll be supporting those endpoints would come from both.

Patients or families.

the investigator or a psychologist. So there's three different types of evaluators. So we think we can look at the synchrony between different evaluators and how they're looking at these with different end points. We hope this will be a robust assessment of how the drug's doing.

The investigator or a psychologist so there's three different types of evaluated. So we think we can look at the synchrony between different evaluated and how they're looking at these different endpoints. We hope this will be.

A robust assessment of how the drug is doing.

So with regard to where we are, the point of this program is to kind of get dosing and titrate dose until we see sufficient efficacy that we would separate from placebo in a trial and be a substantial clinical benefit to patients. And we'll see at that point, we look at that data, if we have achieved that level.

So with regard to where we are the point of this program is to kind of get dosing and titrate dose until we see sufficient efficacy that we would separate from placebo in a trial and be a substantial clinical benefit to patients.

And we will see at that point, we look at that data if we're if we achieve that level.

If we are close to it or at that level, we expect that we would expand the cohort and actually have more patients beginning at the new dose level that we've established and move forward. Now, you asked how are we going to know when we got to the dose? I'm guessing by mid-year we'll have a sense for the dose, but it could be that the expansion cohort will help.

If we are close to it or at that level, we expect that we would expand the cohort and actually add more patients beginning at the new dose level that we had established and move forward and you asked how are we going to know when we got to the dose.

I'm guessing by mid year, we'll have a sense for the dose, but it could be the expansion cohort will help.

Identify or verify that higher level. The idea is to try to tune up the efficacy and manage within what we consider safe dosing range.

<unk> verify that higher level. The idea is to try to tune up the efficacy and manage within what we consider safe dosing range.

That would allow us to see results later in the year regarding that dose.

And it could be that we deal with a young dose, an older dose, or it could be something else we do. But the idea is we're going to learn about how to dose and get an idea of what the optimal dose range is. But we're really encouraged so far that we're not seeing anything at all with the risk of a lower extremity event. And so we're encouraged. We're seeing activity. And we think we just need to work into the deeper in the therapeutic range as we move forward. So we're excited about potential with Angerman. Thank you very much.

And it could be that we deal with a young does an older dose or it could be something else. We do but the idea is we're going to learn about how to dose and get an idea of what the optimal dose ranges, but we're really encouraged so far that we're not seeing anything at all with the the risk.

Lower extremity event and.

So we're encouraged we're seeing activity and we think we just need to work into the deeper in the therapeutic range as we move forward. So we're excited about potential with instrument.

Great. Thank you very much.

Thank you and our next question comes from the line of Casino.

Hamid with Bank of America. Your line is open. Please go ahead. Hey guys.

Commented with Bank of America. Your line is open. Please go ahead.

Hey, guys. Thank you for taking my questions.

Just one point of clarification for Angelman's. Emil, can you just remind us about whether or not you will be able to redose those original five patients that you had on drugs? If you don't know yet, is that going to be part of the discussion with the agency? What would you need if it's not been decided yet to get them comfortable with redosing? And then secondly, for Epsa, what would you need?

Just.

One point of clarification for Angelman.

Can you just remind us about whether or not you will be able to re dose those original five patients that you had on drug.

If you don't know yet is that going to be part of the discussion with the agency what would you need if it has not been decided yet to get them comfortable with re dosing and then secondly for F. Kiva.

Can you talk about where, you know, in a little bit more detail, the synergies are between the products that you currently market and what you would need to build out to market at HOFH.

Can you talk about we're a little bit more detail. The synergies are between the products that you currently market and what you would need to build out to market HOS H. Thanks.

Very good. Thanks, Tazeen. So for Angel Men, we're obviously very interested in redosing those original five. So are those families because they had seen so much. And to have that pulled away is, of course, been tough for them. And so they're anxiously waiting. Our belief is we need two things in order to go back to the agency.

Very good thank <unk> so for Angelman, we're obviously very interested in re dosing those original five so are those families because they had seen so much.

That pulled away has of course been tough for them and so they are anxiously waiting our belief is we need two things in order to go back to the agency.

We want to collect data from the XUS program that's ongoing right now to help look at the dose and retention method, help verify it.

We want to collect data from the ex U S program is gone going right now to help look at the dosing regiments deterioration method.

and just to show that we can dose safely. The second thing...

Verify it.

And just to show that we can dose safely.

Second thing.

we are doing some evaluations on immunological response and other things which will show that there is no immunological issues at all, which I think was part of the original concern on redosing. With those two elements in hand, we'd expect to go to the agencies in this year, middle of the year.

Because we are doing some evaluations on immunological response to those things, which will show that there is no hematological issues at all which I think was part of the original concern on re dosing with those two elements in hand, we would expect to go to the agencies.

This year <unk> here.

and would seek a plan to re-dose those patients and get them back on treatment. And we'd hope that that also eventually gets essentially the world program, the US, ex-US programs aligned in terms of dosing and administration. So we think we want to have some of the data from these next set of patients as well as this additional evaluation of those five patients in order to get to the next step on re-dosing.

And would seek a plan to re doses patients get them back on treatment and.

And we would hope with that also da Vinci get essentially the World program. The U S. Ex U S programs align in terms of dosing and administration.

So we think we want to have some of the data from these next set of patients as well as the additional evaluation of those fives in order to get to the next step on re dosing.

So I'll have Keith.

Rare disease launches have some very common elements. There is certainly a detailed medical kind of knowledge base thing, but there is the reimbursement and country management piece, which is very common. And rare disease products like this always, in Europe particularly, have key centers that are the K-opin leaders run centers or centers of excellence are defined by the government.

Rare disease launches or have some very common elements. There is certainly a detailed medical kind of knowledge base thing, but there is the reimbursement and country management piece, which is very common and rare disease products like this always in Europe , particularly have key centers that are the key opinion leader run.

Our centers of excellence are defined by the government.

And therefore, it really is a very easy orphan model to go out and with a small number of field people manage a limited number of centers. So we're very comfortable that the basic inner workings of supply, medical affairs, as well as reimbursement are things that we can use and we'll have a very limited number of growth in people that would go to those centers.

And therefore, it really is a very easy orphan model to go out and with a small number of field people manage a limited number of centers. So we're very comfortable that the basic inner workings of supply medical affairs as well as reimbursement are things that we can use and we will have.

Very limited number of growth and people that would go to those centers.

The thing that will also happen is that the thing that will also happen is that EPCISA will enable us to go to more countries in Europe , which will expand our footprint a bit, which will allow us to gain revenue for more countries than we currently are. And so I think that's where we will actually gain benefit from EPCISA, which will set us up for the rest of the other programs we have.

The thing that will also happen as of Keith will enable us to go to more countries in Europe , which will expand our footprint a bit which will allow us to gain revenue from more countries.

We currently are and so I think that's where the.

We actually gained benefit from <unk>, which will set us up for the rest of the other programs we have.

with the work we will do. So we're comfortable that we can leverage. We'll we some growth, but we think we'll get a lot of benefit from the team we have who can move on to working at KISA.

With the work we will do so we're comfortable that we can leverage.

Some growth, but we think we will get a lot of benefit from the team we have who can move on to working of chiesa.

Remember, F-KISA and H-O-F-H is still a lipid metabolism disorder. And while there may be sometimes different doctors involved, it is fundamentally a genetic metabolism disorder and our team is well capable of doing it. The other thing I'll point out is because it's such a common, really well-known disease area, it's not as hard as some rare disease areas, right? Everyone knows about LDL. Everyone knows about diagnosis of this disease. It's not like a mysterious disease, which might be more challenging.

Remember <unk>.

<unk> is still a lipid metabolism to order because disorder and while there may be sometimes different doctors involved it is fundamentally a genetic metabolism disorder in our our teams well capable of doing it. The other thing I'll point out is because it's such a common welling really well known disease area, it's not as hard as some rare disease areas right everyone knows about LDL.

Everyone knows about diagnosis of this disease is not like a mysterious disease, which might be more challenging here.

Here, the patients are known. They already go to places.

Here is the patients are known they already go to places. The challenge is just finding them get them on drug in the major centers, who won't take a lot of people will be will be efficient in how we setup commercialize of chiesa.

challenge is just buying them, get them on drug, and if they're at the major centers, it won't take a lot of people and we'll be sufficient in how we set up commercialize at KESA.

Okay. Thank you.

Thank you and our next question comes from the line of Corey Kazimov with JP Morgan. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Cory CASM off with Jpmorgan. Your line is open. Please go ahead.

Hey, good afternoon, guys. Thanks for taking my question. Two for me as well. I guess first, just to follow up on the ESKISA topic, can you just talk a little bit more about the anticipated cadence of countries coming online here? Do Canada and LATAM potentially contribute in 2022, or should we think about these as more of a 2023? And then to change it from Angelman, can you talk about what we might learn?

Hey, good afternoon, guys. Thanks for taking my questions. Two from me as well I guess first just to follow up on the <unk> topic can you just talk a little bit more about the anticipated cadence of countries coming online here I do Canada, and Latam potentially contribute in 'twenty, two or should we think about these as more of a.

2023, and then to change it from Angelman can you talk about what we might learn from the phase II dosing update forced to choose a mab or UX 143 in the second half of this year.

from the phase two dosing update for cetruzumab or UX 143 in the second half of this year. Do we get like a full on safety and efficacy update around the various doses or is it just more like the dose you chose and the plan for phase three? Thank you.

Can we get like a full on safety and efficacy update around the various doses or is it just more of like the dose you chose and the plan for phase III. Thank you.

Okay very good so im chiesa.

There is a sequence that usually people work through in country by country and I probably wouldn't go through that at this moment, but obviously in Germany you can launch more quickly, but other countries like France and Italy have a process we have to work through and we're going to work through the filings and timing of these things to manage

There is a sequence that usually people worked through in country by country.

Probably wouldnt go through that at this moment, but obviously in Germany, you can launch we're quickly but other countries like France, Italy have a process, we have to work through and we're going to work through the filings and timing of these things to manage the pricing process to get through it and to try to achieve consistent pricing across the region.

the pricing process and to get through it and to try to achieve consistent pricing across the region. So I won't go through it right now, but 2022 will be spent primarily filing reimbursement and beginning the process of getting reimbursement in these countries.

So I won't go through it right now, but 2022 will be spent primarily filing reimbursement and beginning the process of getting reimbursement in these countries and ultimately Germany at some point is the one country you can launch sooner and of course that would be something we would do on our plan with regard to Canada and Latam.

And ultimately, Germany at some point is the one country you can launch sooner. And of course, that would be something we would do in our plan. With regard to Canada and LATAM, this still requires filing and approval. So it's obviously not gonna be a big revenue generator in this year.

This still requires filing an approval. So it's obviously not going to be a big revenue generator in this year.

Canon and LATAM is also right now launching Joel Jolie. And LATAM, Chris Veed is still in the beginning of its growth. So they have plenty to do there. But EPCISA will fall in after that. But this year will be more about driving Europe . Again, we'll get the filings in for the rest of Western World for EPCISA.

Canada and Latam is also right now is also launching Joel <unk>.

And Latam crispy Theres still in the beginning of its growth. So they will have plenty to do there, but Keith will fall and after that but this year will be more about driving Europe again, we will get the filings and for the rest of the.

Western World Chiesa.

Now for the next one, was it both UX 143 and Angermann? Was it both or just D-SPARK 143? So 143... I kept hearing Angermann all the time. Maybe I'm kind of dreaming it now. So UX 143, look it's a pretty simple...

Now for.

The next one or was it both UX $1 <unk> was it both or just equal to <unk> 43 to one.

Yes.

Yes hearing agent all the time, maybe I'm kind of $3 million.

Okay.

The <unk> III.

Look it's a pretty simple story.

They already proved that 20 mckeel works quite well, right? We know that already.

They are already proved 20 kilo works quite well right. We know that we're in.

We're now going to young kids, so we're going to test a higher dose.

Now going to young kids, so we're going to test a higher dose.

and that dose and kind of compare. And the purpose is really fine tuning it. It's not like we don't know. We know the dose is probably 20. The question is do you need to go hire some little kids? That's all. And so what we're going to do is try to figure out is maybe the five-year-old needs to run 40 and the old ones are on 20, you know, and maybe somewhere in between. So we're going to kind of look for how do we assess drug distribution, pharmacogenetics, and other things that we can do to help us.

And that dose and kind of compare and the purpose is really fine tuning is it's not like we don't know we know the dose is probably 20 <unk>. The question is do you need to go higher.

That's all and so where we're going to do is try to figure out as maybe the five year old <unk> 40, and the old ones are on 'twenty and maybe somewhere in between so we're going to kind of look for how do we assess drug distribution pharmacodynamic effect of <unk>.

at different ages and doses and just create a dosing algorithm. I think it would last as a dose as a dosing algorithm to how to optimize for age. And based on P1P which not...

Ages and doses and just create a dosing algorithm I think it would lessen that OS is the dosing algorithm to how to optimize for age and based on <unk>, which in our hands.

showed, at least in the hands of the study, excuse me, has showed a really good correlation. So that's kind of what we're...

At least in the hands of the study excuse me have showed a really good correlation so thats kind of what were expecting we would put out a significant data to say here's what we're doing in our dosing algorithm will talk at a high level about dosing, we probably would not provide great detailed data because it's the middle of a blinded study and so we will have some restrictions on how much detail we can.

expecting. We put out a significant amount of data to say here's what we're doing in our dosing algorithm.

at high level about dosing, we probably would not provide great detailed data because it's the middle of a blinded study. And so we'll have some restrictions on how much detail we can provide, but it should be enough to say

drugs working, we figured out how we're going to dose, and then we're heading to phase three. And I think that would be an important update for the program. OK.

Provide but it should be enough to say.

Drugs working we figure out how we're going to dose and that we're heading into phase III and I think that would be an important update for the program.

Okay. That's very helpful. Thank you.

Thank you. And our next question comes from the line of Chris Raymond with Piper Sandler. Your line is open. Please go ahead. Yep, thanks. I've also got a couple of non-angelman's questions if that's okay. Maybe just the first one, you know.

Thank you and our next question comes from the line of Chris Raymond with Piper Sandler. Your line is open. Please go ahead, yes.

Yeah. Thanks, I've also got a couple of non Angelman questions. If that's okay.

Maybe just the first one.

Speaking of the Regeneron deal, I think you've highlighted Amyl before. The second drug in that, potentially second drug is garitosumab.

Speaking of the Regeneron deal I think you've highlighted <unk> before the second drug in that potential.

Potential potentially second drug is <unk>.

You know, just Regeneron, I guess, ran into some issues with when they were developing some fatal SAEs at the end of, I guess it was 2020, and they kind of went silent on it. But just to get into this, it's not clear, I guess, that these deaths were treatment-related, but there still seems to be a safety signal. Maybe just curious, if you could maybe expand on what you see with that molecule, AMOL, in terms of the path forward.

Regeneron I guess ran into some issues with when they were developing with some fatal.

At the end of I guess, it was 2020 and they kind of went silent on it but just to get into this it's not clear I guess that these deaths were treatment related.

But theres still seems to be a safety signal maybe just curious if you could maybe expand on what you see with that molecule a mall in terms of the path forward.

And then just maybe a follow up on Corey's question on Citrusimab.

And then.

Just maybe a follow up on <unk> question, So curious on that.

I think I've heard you say in the past, you know, frame this as maybe an opportunity that when you compare it to XLH, that the demand might even be greater for treatment. Can you just, you know, high level, maybe expand on that a little bit in terms of the market opportunity that you see and just kind of thinking about that as a setting up as a big catalyst in the next year, or end of this year, I guess.

I think I've heard you say in the past you frame. This is.

Maybe an opportunity that when you compare it to XL H.

The demand might even be greater for treatment.

Can you just high level, maybe expand on that a little bit in terms of the market opportunity that you see just kind of thinking about that as a setting up as a big catalyst in the next year or end of this year I guess sure.

So I'm greeted now by, obviously I need to defer to Regeneron on details of their program book. What I can say is we evaluated and the deaths they had in their study, some very advanced patients who have scores were very advanced.

So green doesn't have obviously, a need to defer to regeneron and details of their program, but what I can say is we evaluated and the desk.

Having their steady some very advanced patients who have a scores were very advanced.

We look at all that and our conclusion is the drug is not the cause of those, that they are just very sick people and have advanced disease and that is why we're comfortable with what is going on.

And.

We look at all of that our conclusion is the drug is not.

Cause of those they are just very sick people in advanced disease and that is why we're comfortable with what is going on.

The drug may have events, we're not going to talk through them all, but what I can say to you is its effect.

The drug may have events, we are not going to talk through them, all but what I can say to you is its effect on diseases. So profound disease. So horrible that we feel confidence that drug that should get approved and right now to regeneron is doing their work on developing the development strategy and I would defer to them on that development strategy, but we're confident there is good.

on disease is so profound, disease so horrible, that we feel confident it's a drug that should get approved.

Right now, where Generon is doing their work and developing the development strategy, and I would refer to them on that development strategy. But we're confident there's a good product in there from our look at things.

And there from our look at things.

For the truth Mab.

The OI patient population that can be treated as both type 1

The Oi patient population that can be treated us both type one as well as type threes and type force now if you look at the tide type one have fractures and there can be a variable degree some people have occasional fractures and have.

as well as Type 3s and Type 4s. Now, if you look at the types, Type 1s have fractures and there can be a variable degree. Some people have occasional fractures, some have casualties but one person has some minor injuries, it can be a sharp 1600 degree c

you know, more than occasional, more significant. So some fraction of those patients are really having more issues. Type 3 to type 4 are physically more devastated patients, and their bodies are disintegrating. Okay, those patients are far more advanced and impaired than, let's say, a child with XLAH, right? These kids end up in wheelchairs significantly compared.

More more than occasional more significant fluids. Some fraction of those patients are really having more issues tied to either <unk> or <unk>.

We're devastated patients and their bodies are disintegrating in those patients.

Far more advanced in impaired than let's say a child with X sight right. These are kids ended up in wheelchairs significantly compared kids right. There are devastated not just crooked-leg youre talking about burnt bodies right. So there's no doubt the type III for our horrible and even with this phosphate to whatever it is being done with them now is nowhere.

kids, right? They are devastated, not just crooked legs. We're talking about

bent bodies, right? So there's no doubt that type 3 and 4 are horrible and even with bisphosphonates and whatever is being done with them now is nowhere close to adequate treatment. So we think there's a very high need in the OI population.

Close to adequate treatment. So we think theres, a very high unmet need in the <unk> I'm sorry in the in the Oi population.

And we've been looking the last few years for something better. And what we've been impressed with is that they're among anabolic agents, antiskerostin.

And we've been looking glass year for something better.

What we've been impressed with is that they are among anabolic agents anti score Austin.

is very potent and has the biology sufficient to basically normalize the strength of the bones in models. And the drug in their study showed dramatic improvement in bone density in the lumbar spine, which is one of the places that type 3 and 4 patients disintegrate. Their spines essentially collapse and disintegrate.

Is very potent and has the biology sufficient to basically normalize the strength of the bond in models and the drug in their study showed dramatic improvement in bone.

Density in the lumbar spine, which is one of the places the type three and four patients disintegrate their spines essentially collapsing disintegrate.

this drug had 8 to 10 percent bomerular density improvement in just one year, which is more than double any other anabolic agent in the lumbar spine. So we think that the potency in improving lumbar spine, for example, for young patients would be profound and the strength then could change our future from one of constantly broken bones and declining function to one of stabilized and improved growth and function. So we're...

This drug had 8% to 10% bone marrow density improvement in just one year, which is more than double any other anabolic agent in lumbar spine. So we think that the potency and improving lumbar spine for example for our young patients would be profound and the strength then achieved could could change our future from one of constantly broken bones of declining function to one state.

<unk> and improved growth in function. So we're we believe given that severity and unmet need there'll be a big driver, but on top of that when you talk to kols, especially the larger kols.

We believe given that severity on the knee, they'll be a big driver. But on top of that, when you talk to KOLs, especially the larger KOLs, they generally have 50 to 100% more OI patients than XLAH patients in their clinic.

They generally are 50% to 100% more <unk> patients and <unk> patients in their clinic.

And so the 60,000 prevalence population ROIs probably could be higher than that. We think there's about 50,000 XLH in that same population, but it could very well be there's more ROI than XLH by a significant amount. And that's why if you add that on with a high amount of need, we think it's a population needing our help, needing a new drug, and we're in good position to get there with this one.

And so the 60000 prevalent population realized probably could be higher than that we think theres about 50000 escalation that same population, but it could very well be theres more oi than XL age by a significant amount and thats why we add that on with a high unmet need we think it's a population needing our help needing.

A new drug.

And we're in good position to get there with this one.

Great. Thank you very much.

Thank you and our next question comes from a line of yarn we're with Cowan. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Yaron Werber with Cowen. Your line is open. Please go ahead.

Hi, this is Brendan on for your own. Thanks for taking the question guys. Just one quick one on Chris feeder understand the rest of world and person can be a bit choppy. But obviously, it was a pretty impressive quarter quarter jump in North America. I just want to see maybe what drove that in Q4 and how we should think about it in context and maybe moving forward this year.

Hi, This is brendon on for you Ron Thanks for taking the questions guys.

One quick one on Chris' feeder understand the rest of world and broken it can be a bit choppy, but obviously it was a pretty impressive quarter over quarter jump in North America I just wanted to see maybe what drove that in Q4, and how we should think about it in context and maybe going forward. This year.

And then just a quick one on the GSD3 readout in the second half. What kind of data could we maybe expect and how many patients are you expecting by then? I wasn't sure if you said we'd get repeat dosing data or if it'll just be the sad patients. Thanks very much. All right. Thank you, Bren. I'll let Eric handle the Chris Vida quarter on quarter.

And then just a quick one on the GSD III readout in the second half.

What kind of data can we may be expecting some how many patients are you expecting by then I wasn't sure. If you said, we'd get repeat dosing data or if it will just be the sad patients. Thanks, so much.

Thank you Brandon I'll, let Eric handle the crispy the quarter on quarter.

number question and then Camille can handle GSD3 patient briefly.

Number question and then Camille can handle GST three patient.

Thank you.

Yeah, we had a strong fourth quarter.

Yes.

We had a strong fourth quarter.

you know, it surged following a summer lull, which was driven by the Delta virus, where there was a lot of lower activity in the mid-year with patient volumes going into office.

Serge following.

Summer lull, which was driven by the Delta virus, where there was a lot of lower activity in the mid year with patient volumes going into offices.

So we saw a surge at the latter part of the year as we rebounded coming out of that Delta variant.

So we saw a surge at the at the latter part of the year.

As we rebounded coming out of that Delta.

Delta variant.

Great. Thanks for the question about UX053, our GSD3 program. Yes, we will have data on our open-label single ascending dose portion of the study in the second half of 2022. Approximately 8 to 10 patients with data.

Oh, great. Thanks for the question about <unk> program, Yes, we will have data on our open label single ascending dose portion of the study in the second half of 2022.

Approximately 8% to 10 patients data.

As the name suggests, the doses will be escalated.

As the name suggests the doses will be escalated.

after by cohort by cohort. And so we'll have information first and foremost on the safety, as well as some additional pharmacodynamic and initial clinical activity.

After by cohort by cohort until we will have information first and foremost on the safety as well as some additional pharmacodynamic and initial clinical activity data from from that portion of the study the repeat dosing portion of the study will be blinded randomized and blinded. So we won't have.

from that portion of the study. The repeat dosing portion of the study will be blinded, randomized and blinded. So we won't have data until that portion has been completed, but we'll certainly give you an update on where that portion stands in the second half of the year as well.

Data until that portion and completed but we'll certainly give you an update on where that portion stance in the second half of this year as well.

Okay, great. Thank you.

Thank you. And our next question comes online of Maury Raycroft with Jeffries. Your line is open. Please go ahead.

Okay.

Thank you and our next question comes from the line of Maury Raycroft with Jefferies. Your line is open. Please go ahead.

Hi, congrats on the progress and thanks for taking my questions. I was going to ask one on Angelman. Wondering what the cadence of enrollment could look like in the United States. How many patients do you plan on enrolling in the US at 2 mgs and will you have ability to adapt dosing or expand the study in the US during the four month time frame? I guess could there be a US dosing update before your mid-year data update?

Hi, Congrats on the progress and thanks for taking my questions.

I was going to ask one on the Angelman.

I'm wondering what the cadence of enrollment could look like in the United States.

Many patients do you plan on enrolling in the U S. At two Megs and where you have the ability to adapt to dosing or expand the study in the U S. During the four month timeframe I guess could there be a use dosing update before year mid year data update.

Yeah, very good. The patients are essentially, I think they're essentially enrolled now, right? Clerk enrolled. So we're enrolled. The 4 patients that were planned for 2 meg. So. That's already there and then.

Yeah very good.

Patients are essentially I think the assumption enrolled around the world. So were enrolled before patients that were planned for two Mig So that's already there and then.

We're playing is we're letting them go and get started and was an agreement with FDA just to get started. I think our plan was to take enough data from our US to come back to the agency. And look through what we can do to update the US program. I would expect that somewhere toward the middle of the year. I don't know that by the update we would have changed the FDA.

We're playing we're letting them go and get started and it was an agreement of the FDA to get started I think our plan was to take enough data from our ex U S to come back to the agency.

And look through what we can do to update the U S program I would expect that somewhere towards the middle of the year I don't know that by the update we would have changed the FDA.

protocol for the US yet, but we're planning to try to get as much data from the current set of patients so that we go back to the agency with a very crisp single package and get their agreement. And so once we have the other safety information that we hope to go back and.

The protocol for the U S yet, but we're planning to try to get as much data from the current set of patients. So that we go back to the agency with a very crisp single.

Package and get their agreement. So once we have the other safety information that we hope to go back in.

And align the US protocol with the X, US we'd have to deal with patients who are on to make. By that point, they would probably have their doses completed, but we would probably expect to enroll them in. As as participants in the next in the cohort of the expanded protocol that we're doing. So.

And align the U S protocol with the X to us we'd have to deal with patients who are on two Mig.

By that point, they will probably have their doses completed, but we would probably expect to enroll them in.

As participants in the next in the cohort of the expanded protocol that we're doing so.

We can't tell you exactly, but we're going to try to get to that certainly mid year.

We can't tell you exactly but we're going to try to get to that certainly mid year.

Got it. That's helpful. And then I just had a quick question on the FOP option with Regeneron. I guess for EF-QISA, I'm wondering if there are near-term obligations with launches that may factor into negotiations related to the exclusive FOP app.

Got it that's helpful and then I.

Just had a quick question on <unk>.

Option with Regeneron I guess.

For it.

I'm wondering if there are near term obligations with launches that may factor into negotiations related to the exclusive <unk> option.

Well, the two things are not really tied to each other. There are certainly, in our agreement with Onyeth Kiesa, people were both talking about what you are thinking or about whatever you want to say to them,

Well the two two things are not really tied to each other there are certainly in our agreement with <unk> Keith will have.

aspects of performance that we need to execute on and that's all agreed to. But the option doesn't depend on those, it just is what our requirement is. The option will depend on as point in time, it will provide information that they have and what the development plan is and we'll have the ability to opt in and then start to share some of the development costs for the greatest map. So, the two things are not related to each other at this point.....

Aspects of performance that we need to execute on and Thats all agreed to but the option doesn't depend on those it just.

Put a requirement in the option will depend on as point in time, we will provide information that they have and what the development plan is and we'll have that.

Ability to opt in and then start to share some of the development costs for our greatest Mab.

So the two things are not related to each other.

At this point.

Got it okay. Thanks for taking my questions.

Thank you and our next question comes from the line of Degan Haw with Stiefels. Your line is open, please go ahead.

Thank you and our next question comes from the line of Dan <unk>.

With Stifel. Your line is open. Please go ahead.

Great. Good afternoon. Thanks for taking our questions. I'll also stay away from Angelman tonight. One, just on FQISA.

Great. Good afternoon, thanks for taking our questions.

So stay away from Angelman Tonight, one just on F keys.

It seems to be more commercially driven, but I was wondering, Emil, if I could get your take on anti-PTL3 targeting gene editing approach and whether or not you consider that before you went with Efkiza. And then secondly on satruzimab, um,

It seems to be more commercially driven but I was wondering if I could get your take on <unk> III targeting gene editing approach and whether or not you consider that before you went with <unk>.

And then secondly on <unk>.

I guess can you remind us in terms of how you're thinking powering wise that you're going after fracture versus the bone density that was measured in the asteroid study? Thank you.

I guess can you remind us in terms of how youre thinking powering wise that youre going after fracture versus the bone density that was measured in the asteroid study. Thank you.

Okay. So in the commercial side...

Okay.

So in the commercial side.

There's obviously other ways to knock out AnJ-PTL3, but the antibodies in hand is very safe, works well.

There's obviously other ways to talk about <unk> III, but the antibodies in hand is very safe worked well.

and genetic knockout strategies have just submitted the very first few patients.

And Jean netting knockout strategies.

Yes.

The very first few patients.

Which is very exciting, but to me is going to take years to get through.

Which is very exciting to me is going to take years to get through.

The goal people have in trying to do this is certainly not treating HSH and gene editing. But right now we're watching the gene editing field. We're a company that likes to take advantage of platforms, but does have to develop them ourselves. So in our view, what we needed was not another early stage program to experiment with, but a product that we could sell that worked. And down the road, if your point is, well, could something replace

The goal of people have been trying to do this is certainly not treating HSH in gene editing, where right now we're watching the gene editing field.

We're a company that likes to take advantage of platform, but <unk> have to develop them ourselves. So in our view what we needed was not another early stage program to experiment with a product that we could sell that worked in down the road. If your point is well could something were place.

for DANJ PTL33 maybe.

This is.

<unk> four <unk> hundred <unk> maybe.

But is it really in the next few years? Is it ten years? How long? Could be a while. And honestly, very few people are going to spend all the money on gene editing to treat that few numbers. So, if they're trying to do the bigger market, at some point maybe that will happen. But right now we feel comfortable this is a program we can sell now that works.

But is it really in the next few years or is it 10 years, how long could.

Could be a while and honestly very few people are going to spend all the money on gene heading to treat that few number so they're trying to do the bigger market. Some point, maybe that will happen, but right now we feel comfortable as the program. We can sell now that works well.

works well, it's pretty convenient, doesn't have any unknown genetic...

Well, it's a pretty convenient doesn't have any unknown genetic issues that are yet to be figured out.

issues that are yet to be figured out and so we're comfortable there's a good place for it in our portfolio at this point in time.

And so we're comfortable there is a good place for it in our portfolio at this point in time.

But we're watching Gene Edding just like all of you, and they'll have ups and then downs.

But we're we're watching gene editing just like all of you and they will have ups and downs.

For you it's 143.

Boveral density by the FDA is generally not considered sufficiently clinical in their mind. There have been situations where it didn't correlate well, although I think with anabolic agents it correlates better with outcomes.

Overall density by the FDA are generally not considered sufficiently clinical in their mind and there have been situations, where it didn't correlate well, though I think with anabolic agents it correlates better with outcomes.

So their requirement was to have clinically observed fractures to be the primary end point.

Their requirement was to have clinically observed fractures to be the primary endpoint what.

What we know from the data in asteroid is that there were trends to fracture improvement. The study was not very big and didn't have enough time. But our view of it was that the bone and dental density improvements in the trend and fractures that we're seeing in the higher dose patients.

What we know from the data an asteroid that there were trends to fraction proven the study was not very big and didn't have enough time.

But our view of it was that the bone mineral density improvements in the trend and fractures that we're seeing in the higher dose patients.

would be clinically important and we feel comfortable that will work. Second thing, remember that asteroid study was adult.

Would be readily it would be clinically important and we feel comfortable that work second thing remember that asteroid study was adult adult bonds don't respond like Kid bones, and Thats why I remember in <unk>, we got out of adults and peds and peas are what drive the powerful efficacy story same thing is going to be true for <unk> III.

Adult bones don't respond like kid bones, and that's why I remember with XLH, we got out of adult when it peed.

what drives a powerful advocacy story. Same thing is going to be true for UX 143. Kids bones respond much greater, much faster, and will remodel faster and build bone faster. And so I'm very confident that in that group that we can improve fractures even more readily than you would in adults.

Kid advanced respond much greater much faster and we will remodel faster and build bone faster and so I'm very confident that in that group.

That we can improve fractures, even more readily than you would in adults.

So that's why we're pretty comfortable. That was true, by the way, because everything we did in kids worked faster and more powerful. In fact, people said it should take two years to see bone change, remember, in XLH. But in kids...

That's why we're we're pretty comparable that was true by the way Im sure, but everything I think we didn't kids work faster and more powerful.

In fact people said it should take two years to see bone changes amendment escalation, but in kids.

we actually got 80% of the benefit in nine months only. Right? That was unexpected to some, but as a pediatrician, I like kids because they get better. That's why I went into pediatric medicine originally. As opposed to a granular eye.

We actually got 80% of the benefit in nine months only.

That was unexpected to some but as a pediatrician I like kids, because they get better and that's why I went into pediatric medicine originally.

As opposed to us.

Alright. Thanks.

Thanks very much.

Thank you and our next question comes from the line of Solveen Richter with Goldman Sachs. Your line is open. Please go ahead.

Good.

Thank you and our next question comes from the line of <unk> Richter with Goldman Sachs. Your line is open. Please go ahead.

Hey, thanks for taking your question. This is Elizabeth on First Alvein. For your 2022 CRISP-FETA guidance, just wondering if you could comment on the breakdown you expect may come from North America versus the other rest of world geographies.

Hey, Thanks for taking our question. This is Elizabeth <unk> for Celgene for your 2020 to Chris' guidance I was wondering if you could comment on the breakdown you expect may come from North America versus the other rest of world geographies.

Well generally we don't make that breakdown for the sole purpose of allowing Eric the room to do what he has to do to get the sales there. But Eric I don't know if you want to comment I don't think we've made the breakdown of the past.

Well generally we don't make that breakdown for the sole purpose of allowing Eric the room to do would have to do to get the sales there, but Eric I don't know if you want to comment I don't think we've made the breakdown in the past.

I'll comment just a bit and then just from the numbers that you can jump in. All right. Yeah. So, I mean, we put in the press release that the North American territories were 171 million last year and other product sales, although we didn't break that down, but it's mostly crispy coming from Latin America, was about 21 million. So that gives you the magnitude of difference within that guidance.

I'll comment just a bit and then just from the numbers Alright, alright, yes.

The press release that.

In North America territories for $171 million last year and other product sales, although we didn't break that down but mostly Chris.

Christy that right coming from Latin America with about 21 million. So that gives you that point the magnitude of difference within that guidance.

So we continue to see very strong growth of Crispida in Latin America, but generally the biggest growth and the largest numbers clearly come from North America. Eric, I don't know if you want to add anything.

We continue to see very strong growth that could be that in Latin America, but generally the biggest growth in that number is clearly north America.

Eric you want to add anything more.

Exactly what else what I'm, saying.

Oh, sorry. Just kidding. We're set. So Elizabeth, there's your answer.

Okay Alright.

Perfect.

Is that there is your answer.

Thank you Greg.

Thank you. And our next question comes from the line of Joseph Swartz with SBB Securities. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Joseph Schwartz with SBB Securities. Your line is open. Please go ahead.

Thanks very much. At the FAST conference, I guess I'll preface this by saying my first question is on Angelman and my second is not.

Yes.

Alright, thanks very much.

At the first conference I guess I'll preface this by saying My first question is on Angelman and my second is not.

At the FAST conference late last year, Dr. Dindo emphasized the value of preclinical models for Angelman. And so I was wondering if, particularly the PIG model, and I was wondering if you've studied GTX 102 in the PIG model and if so, what did you see with respect to the therapeutic index and dose response of GTX 102? And then is any of that of value and... 93% of magnificationurtles 36% are notmelnation maybe? And we're happy statement having

But.

At the SaaS conference late last year, Dr. Jindo emphasize the value of.

Preclinical models for enrolment.

And so I was wondering is particularly the pig model and I was wondering if you've studied gtx 102 in the big model and if so what did you see with respect to the therapeutic index and dose response of Gtx 102, and then is any of that with value and.

working out to be in line with what you're observing in patients now.

Working out to be in line with what you are observing patients now.

Yes, well, Dr. Dindo, of course, at Texas A&M would...

Yes.

Didn't know of course that Texas A&M wood.

we talked about animal models being the ag school it is, but and the pig was more recently developed. So we don't actually have the ggx1 data in the pig. They were developing the pig. They got it done now. But now we're in the clinic. So we haven't gone back to the pig with ggx1. So I couldn't really answer those details.

We've talked about animal models being weak.

The AG school it is but.

And the pig was more recently dropped so we haven't we don't actually have the J T. J code data and the pig they were developing the pig. They got it done now and now we are in the clinic. So we haven't gone back to the pig with <unk>. So I couldnt really answer those details.

I think the pig is interesting because it acts like angelman patients, humans. It has, it doesn't have a stranger anxiety. It will come up to strange where most pigs are reluctant to come up to strangers. So there's these subtle behavioral patterns which are retained, which are interesting. But we haven't done the work yet, but I do think it could be helpful in other work in terms of developing additional improvements to the molecule or other types of approaches.

I think the pig is interesting because it acts like angelman patients humans has it doesn't have a stranger things.

<unk> it will come up to change where most pigs are reluctant to come up to strangers. So theres. These subtle behavioral patterns, which are retained which are interesting.

But we haven't done the work yet, but I do think it could be helpful. In other work in terms of developing additional improvements to the molecule or other types of approaches but.

The truth is that fundamentally pig or whatever or monkey, you gotta deal with human patients to figure out what's happening and so.

The truth is that.

Fundamentally pig or whatever or monkey you've got.

To deal with given patient to figure out what's happening and so.

The biomarker story could also be maybe developed in the pig, but honestly, by the time we figure out a biomarker is validated, we'll have already completed the clinical program. So, the truth is that right now our history and future is dependent on what we do in the clinical program, and the models will help us expand the options we have for the future, but I don't think are going to find the path forward in the clinic.

The biomarker story could also be maybe developed in the pig, but honestly by the time, we figure out a biomarker validated we will have already completed the clinical program. So the truth is that right now our history and future is dependent on what we do in the clinical program and the models will help us expand the options we have for the future.

But I don't think youre going to define the path forward in the clinic.

Okay. And then, given your seamless Wilson disease study, we'll have a couple decision or data points. I was wondering if you can give us a sense of when we might hear something first about the effect and the dose that will be taken into the pivotal portion of the study.

Okay.

And then given Youre a seamless Wilson disease study will have a couple of decision or data points.

Was wondering if you can give us a sense of.

When we might hear something first about the effect and the dose that will be taken into the pivotal portion of the study.

Sure, we will have an interim assessment of the program. But because the blinded program, we won't be able to disclose all the data that we have. But our expectation, now the study didn't start. It's just starting now, so the timeline to get that interim is not going to be this year. Now, because of where we are in.

Sure we will have an interim assessment of the program, but because the blinded program, we won't be able to disclose all the data that we have but our expectation now steady didn't start is just starting now so whats the timeline to get that interim is not going to be this year.

Now because of where we are in time, but.

Our expectation is to be able to know what the dosing response looks like, that the drug is working, that there is an impact on the markers of importance, and that...

Our expectation is to be able to know what the dosing response looks like that the drug is working that there is an impact on the markers of importance and that.

we're choosing a dose and proceeding. So that's the kind of level of granularity probably we provide. And we'll have to be careful about it because we just don't want to have anything that damages the objectivity of the phase three study. But it should be enough to tell you the drug work, here's the dose and we're proceeding to phase three.

We are.

Choosing a dose and proceeding so that's the kind of level of granularity probably will provide and we will have to be careful about it because we just don't want to having that.

Damages the objectivity of the phase III study, but it should be enough to tell you the drug appears to dose and we're seeing the phase III.

Okay, great. Thank you.

Thank you and our next question comes from the line of June Lee with Truist Securities. Your line is open. Go ahead.

Thank you and our next question comes from the line of Jim <unk> with <unk> Securities. Your line is open. Please go ahead.

Hey, thanks for taking our question. For the Angelman data by mid-year, is your goal to have all Canada and UK patients on 14-milligram dose before you top line the data? Do you have sufficient time to get all those patients to 14 milligrams, or do you have the ability to skip a few doses between the starting dose and the maximum 14-milligram dose? And what is your definition of mid-year?

Hey, thanks for taking our questions.

For the Angelman data by mid year.

Goal to have all Canada, and you'll keep patients on 14 milligram dose before your topline data.

Do you have sufficient time to get all of those patients to 40 milligrams or or do you have the ability to skip a few doses between the starting dose and the maximum 40 milligram dose and what is your destination mid year.

Very interesting.

We'll start with the last one. Mid-year is Q2 or Q3.

I will start with the last one mid year is Q2 or Q3.

broad enough to really be annoying to all of you. So that's why we pick it that way. But the truth is we have to get through a number of steps and get the study executed. The study has a protocol where they escalate after two doses and then they can escalate every three months during the maintenance phase further. However, getting the 14 will take a number of months if we were to get there. So your question is, could we just jump doses and...

It's broad enough to really be annoying to all of you. So thats why we pick it that way.

But the truth is we have to get through a number of steps and get the study.

Executed.

The study is a protocol worthy they escalate after two doses and then they can escalate every three months during the maintenance phase further however, getting the 2014 will take a number of months. If we were to get there for your questions can we just jumped doses.

Not a normal clinical protocol to jump doses. So we are going to look at the data we have as we get to mid year and our expectation instead of jumping dose of June is to see where we're at.

Not in normal clinical protocol to jump doses. So we are going to look at the data we have as we get to mid year and our expectation instead of jumping dose of June is to see where we're at and initiate an expansion cohort right, which would allow us to start dosing at a higher level now of dose level, let's say that's cleared by the data so far.

and initiate an expansion cohort, right, which would allow us to start dosing at a higher level now, a dose level, let's say, that's cleared by the data so far, but start at that dose level and now load with four doses at that higher level. So, to get what you're getting at June , by doing that, it will allow us to jump efficacy a little further if we're not at our, where we want to be by the time we're at mid-year and that will allow us to jump the dose.

But start at that dose level and now load with four doses at that higher level. So again, what youre getting at June by doing that will allow us to jump efficacy a little further if we're not at our we want to be by the time, we're at mid year and that will allow us to jump the dose.

A bit higher and continue ahead. We have to work through the safety window and establish that there'd be the window. I think.

A bit higher and continue ahead, we have to work through the safety window and establish that therapeutic window I think.

What we've seen so far, there is a therapeutic window. We just need to figure out on what it will take to get the dose that gives us the kind of efficacy we think would be meaningful for patients.

What we've seen so far there is a therapeutic window, we just need to figure out.

We will take to get the dose that gives us the kind of efficacy, we think would be meaningful for patients. So.

Rather than jumping, well, those patients will continue, we'll add an expansion of coral heart, which will jump up another level and then titrate from there and that will hopefully give us that dose, this dose, somewhere between all that information. We'd expect to have...

Rather than jumping will both page will continue will add an expansion cohort, which will jump up another level and then titrate from there and that will hopefully give us that dose this dose somewhere between all of that information we would expect to have.

clarity later in the year by what we're going to run in phase 3.

Clarity later in the year by what we're going to run in phase III.

And then, quickly, are there any more planned meetings for the Data Safety Monitoring Board? These are not pre-specified.

Got it and then.

Quickly are.

Are there any more planned.

Meeting for the data safety monitoring board or <unk>.

Is there no pre specified.

Yeah, the two pre-specified were related to the further enrollment or expansion of the enrollment. That's all those have happened, but they will meet on a regular rhythm cadence because they need to continuously evaluate safety that's gone going. Of course, if a lower extremity event happened, they would be notified immediately and have an ad hoc meeting, but there is a regular cadence that. That they are going to be doing, but there's no special triggers yet, except a safety event.

Yes.

Two pre specified were related to the.

Further enrollment or expansion of the enrollment and Thats all those have happened, but they will meet on a regular rhythm and cadence because they need to continuously evaluate safety they've gone going of course, if a lower extremity then happen they would be notified immediately and have an AD hoc meeting, but there is a regular cadence.

They are going to be doing but there is no special triggers yet except a safety event.

otherwise it's a regular cadence of meeting as the data goes forward.

And otherwise it's a regular cadence of meeting is the tail that goes forward.

Alright, thank you.

Thank you and our next question comes from the line of Jeff Hung with Morgan Stanley . Your line is open. Go ahead.

Yeah.

Thank you and our next question comes from the line of Jeff Hung with Morgan Stanley . Your line is open. Please go ahead.

Thanks for taking the question. For Apsa, what considerations beyond the indication were there for the partnership, such as, you know, you mentioned geographic expansion to APAC and further into Europe , and then how important is the potential for the expansion?

Thanks for taking the question for Pizza, what considerations beyond the indication we're there for the partnerships such as you mentioned geographic expansion to APAC and further into Europe , and then how important is the potential for the expansion.

Okay.

With regard to considerations, I think the importance for Regeneron was that we commercialize in all the territories, that we support patients in all the countries that are in the trials as well. Because there are some patients that are in the trials that are in the trials that are

So.

With regard to considerations I think the the importance for our Regeneron was that we commercialize in all the territories that we support patients in all the countries that are in the trials as well.

Because there are some patients down.

in South Africa and other places. So, we are going to support, of course, any patients in any country. And there is a requirement that we certainly commercialize in a broad array of countries that we will be working on.

In.

South Africa and other places so we are going to support of course any patients in any country.

And there is there is a requirement that we certainly commercialized in a broad array of countries.

Because Asia is there, we wanted to go into this, if Keith agrees with the tool to actually go and have Japanese patient data in the program.

That will be working on.

Because Asia is an area. We wanted to go into this is Keith.

Tool to actually go and it has Japanese patient data in the program.

And the Japanese KOL involved was very, very positive on the study and very much helped us get it approved in Japan quickly. So we have a package that's already potentially filed in Japan that should get us going in Japan earlier. So that will be part of our immediate expansion of the filing.

And the Japanese coil Kols involved.

Very very positive on the steady and very well to help us get it approved Japan quickly. So we have a packages already potentially file in Japan that should get us going in Japan earlier, and so that'll be part of our <unk>.

Expansion of the filing.

So, beyond that, I don't think that it's worth going into more detail. With regard to the...

So beyond that I don't think it's worth going into more detail with regard to the.

making taking the options, it's really about us looking at where the development program is going and understanding the current data set they have and at that point, which is set by time, we'll sit down and have a discussion with them about going forward. And at this point, I think it's

Making taking the options, it's really about us looking at where the development program is going and understanding the current data set they have.

At that point, which was set by time, we will sit down and have a discussion with them about going forward.

<unk>.

At this point I think it's.

a drug that's doing something very profound and important for these patients.

A drug that's doing something very profound and important for these patients and.

I would say that that effect is so profound that most patients would, I would think, would want to get treated with it. So we're highly encouraged and we would expect to move forward at this point in time.

I would say that that effect is so profound that most patients would I would think we'd want to get treated with it.

So we're highly encouraged we would expect to move forward at this point in time.

And then as a follow up to the question on Latin America, what are the key factors for further growth in Latin America this year?

And then as a follow up to the question on Latin America, what are the key factors for further growth in Latin America. This year.

Well, Latin America is always the story is always we have a great team. By the way, we have like some of the best people in Latin America and that team. They've done this well for a lot of rare disease program. The challenge has always been the politics and the encode that regard to reimbursement.

Well Latin America is always the story has always been we have a great team by the way we have some of the best people in Latin America and that team have done this well for a lot of rare disease program. The challenge has always been the politics in Covid regard to reimbursement.

In Brazil, I think one of the important pieces that we've gotten through the reverse of the process now, setting as a final step. So once that happens, then there'll be a set agreed price and there will be the ability to expand in Brazil further.

In Brazil, I think one of the important pieces that we've gotten through the reverse with process now setting the final steps.

That happens then there'll be a set of reprice and there will be ability to expand in Brazil further.

In other countries, we're certainly working on filings and working on name patient sales and we'll begin adding where we can, working through reimbursement. But we are seeing traction now and growth in Latin America. I don't know if there's anything else, Eric, you might want to add to the Latin America growth story at this point.

In other countries. We are certainly working with working on filings and were going to named patient sales and will begin, adding where we can working through reimbursement, but we are seeing traction now and growth in Latin America I don't know if theres anything else, Eric you might want to add to the Latin America growth story at this point.

No, I think just as similar as we did in North America, in particular in the U.S. with growth, we continue to expand to find more patients as we reached out further into the community setting. Something similar will occur in Brazil, especially as we attain full reimbursement and we can go into full commercialization promotional activities.

No I think just as similar as we did in North America, and particularly in the U S with growth.

Continuing to expand the firing.

More patients.

We reached out further into the to the community setting.

Something similar will occur in Brazil, especially as we obtain full reimbursement and we can.

Go into full commercialization.

Promotional activities.

Yes, I think thats kind of important to Phil Thanks, Eric.

Thank you. And our next question comes from the line of Lisa Baco with Evercore ISI. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Lisa <unk> with Evercore ISI. Your line is open. Please go ahead.

Hi, yeah, just one quick financial question and most of my questions have been answered, but maybe just one then quick one on Angelman. So, can you just give us some parameters to think about?

Hi, Yes, just one quick financial question and most of my questions have been answered, but maybe just one quick one on Angelman. So can you just.

Give us some.

Parameters to think about.

Um, for spend this year, um, I was just looking at your R and D number up a bit. Is that a good run? Right? To think about, or maybe can just walk us through the shape for the year. Especially of R and D thing.

For our spend this year.

I was just looking at your R&D number it's up but is that a good run rate to think about or maybe you can just walk us through the shape of the year, especially if R&D things.

Sure, there's obviously there is some increase of spend as Marty's put out. Marty kind of described it a little more. There have been some 1 time items too in the mix. So Marty, why don't you. Yeah.

Sure.

Obviously, there is some increase in spend as Marty has put out Marty you kind of described it a little more there've been some one time items too in the mix. So Marty why don't you give them.

Yeah, we highlighted the $50 million up front for the Maria collaboration that's in there. But, you know, right now with our development pipeline in late stage programs and our work in gene therapy, etc., we do think we'll have some growth in R&D going into 2022.

Yes.

Yes, we highlighted that $50 million upfront.

And they're right.

Right now our development pipeline in late stage programs and our work in gene therapy et cetera.

Perhaps.

Growth in R&D going into 2022.

Mostly on the R&D line, I would say FPA, other than the focus on F-PISA as we build up reimbursement in multiple countries in Europe , will stay pretty much the same.

Mostly on the R&D line I would say.

Sure.

And then the focus on SG&A.

As we build out the reimbursement in multiple countries in Europe .

we would expect it to continue growth in our area for the next year, for sure.

We will stay pretty much the same.

We would expect continued growth in the next year for sure.

Okay, thanks. And then just on to Angel Minns, are there any like biomarkers or things like that, that you're looking at to help guide you? And you know, that would be sort of

Okay. Thanks, and then just on Q1.

<unk>.

Enrolment is are there any like biomarkers or things like that I think youre looking at to help guide you and that would be.

indicative of our kind of telling with respect to the other metrics you're looking at.

<unk>.

Indicative of our kind of tying with respect to the other the other metrics youre looking at.

Sure, well, first of all, the soluble biomarkers like UB3A, we presented it fast.

Sure.

First of all the soluble biomarkers like <unk>, we presented it fast the fact.

what people thought were UB3A and spinal fluid was probably blood contamination because there is UB3A in blood cells. And so it turned out that trace amounts UB3A found in the spinal fluid may very well be due to leak a little bit of blood into the tap.

The what people thought were <unk>, three and spinal fluid with probably blood contamination, because there is <unk> blood cells and so it turned out the trace amounts of <unk> found in the spinal fluid may very well do.

Leak, a little bit of blood in the tap.

which means that they're probably detecting EV3 in the spinal fluid is not going to be a kind of biomarker, but

Which means that they are probably detecting <unk> three in the spinal fluid is not going to be kind of biomarker, but.

What I'd read directly is to look at the neurophysiology and that's the delta power, EEG.

Redirect Lisa to look at the neurophysiology and Thats the Delta power <unk>.

The EEG is now not dependent on patient's thinking or whatever they're doing, it's looking at neurologic function and what we showed, and there was an update as fast that you guys should look at.

<unk> is now not dependent on patient thinking or whatever they are doing it looking at neurologic function and what we showed in there wasn't updated fast that you guys should look at more detailed data on the <unk> of the patients in the trial looking at Epileptiform and Delta powers showing changes in neuro for us.

more detailed data on the EEGs of the patients in the trial looking at epileptiform and delta power, showing changes in neurophysiology in those patients that were meaningful.

And those patients that were meaningful so.

I think it shows you that it's not just subjective view of the patient that's better. There is neurophysiological evidence. And I would look at that neurophysiology as being probably the best biomarker type information and would tell you that something fundamental is happening and these very abnormal brains are starting to respond differently to stimuli than they did before.

I think it shows you that it is not just subjective view of the patient that better does narrow physiological evidence and I would look at that neurophysiology is being probably the best biomarker type information would tell you that something fundamental is happening in these very abnormal brains are starting to respond differently to stimuli than they did before.

Yes.

Okay. Thank you.

Thank you and our next question comes from the line of Joel Beattie with Baird. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Joel Beatty with Baird. Your line is open. Please go ahead.

Hi, thanks for taking the questions. The first one is on Epson, the outside of the US. After approval, how fast could the ramp up in sales be compared to what might otherwise be typical for rare disease drugs? And then the second question is for Wilson's disease in the stage one part of the trial, how much potential is there at that time to learn about any efficacy on neural endpoints?

Hi, Thanks for taking the questions first one is on <unk>.

Outside of the U S.

After approval, how fast the ramp up in sales be compared to what might otherwise be typical for a rare disease drugs and then the second question is.

Wilson's disease.

Page one part of the trial, how much potential is there that time to learn about any efficacy neuro endpoints.

Okay, so the first question on outside the US was about EPCISA or something else.

Okay. So the first question on outside the U S was about <unk> <unk> or something else.

Yes.

So it's a little hard for us to guide for sales outside yet. I mean, I think this year's going to be about reimbursement in Europe , getting it set and going. And the other countries are going to be somewhat behind them, so I wouldn't be able to tell you much about how the growth is going to be.

Yeah. So it's a little hard for us to guide for sales outside yet I mean, I think this year is going to do our reimbursement in <unk>.

In Europe , getting it set and going in the other countries are going to be somewhat behind them. So I wouldn't be able to tell you much about how the growth is going to be.

but I would expect that you're a.

But I would expect that.

you know, an XUS launch is going to take a couple years of filings and approvals and reimbursement work to get...............

Our Europe .

And ex U S launch, it's going to take a couple of years of filings and approvals and reimbursement work to get dramatically going with this year is all about Europe and Thats, what the team will be focusing on.

dramatically going, but this year is all about Europe , and that's what the team will be focusing on.

With regard to Wilson, there are some neurocognitive Wilson scales that are in the program. However, remember a lot of the patients may not have abnormalities at the beginning, so you're talking about the people that do have score abnormalities.

With regard to Wilson.

Are some neurocognitive Wilson scales that are in the in the program. However, remember a lot of the patients may not have abnormality that that at the beginning so you were talking about the people that do have score abnormalities.

trying to determine their difference would be hard to do on dosing, so we're going to focus the dosing on the biomarkers of copper control. And there's really good data to say that copper control in its various forms should give us the right answer on dosing. And basically what it will really be is have people prime themselves so that we're looking at that.

I am determined there difference would be hard to do on dosing. So we're going to focus the dosing on.

The biomarkers of copper control and theirs.

Really good data to say that copper control in its various forms.

Should give us the right answer in dosing.

And basically I would say to you that if.

all things equal, if the highest dose gives us the highest ceruloplasmin levels, which it likely would, and assuming that it's safe, the same safety as the E13 dose, and I would think the highest dose is going to end up most likely to be the dose.

All things equal if the highest dose gives us the highest gorilla plasma levels, which likely would and assuming that it's safe for the same safety of the <unk> doesn't I would think the highest dose is going to end up most likely to be the dose.

And so there shouldn't be that much mystery because we're pretty clear that in this range that the dose that, you know, in the low E13 range that two E13 should be better than one E13. And we would expect, assuming safety is excellent, that that would end up being coming the dose.

And.

So there shouldnt be that much mystery, because we're pretty clear that in this range that the dose that.

In the low <unk> range that <unk> should be better than 2013, and we would expect assuming safety excellent that that would end up being coming the dose.

But because it's a new treatment first in man, we have to work through the process, right? And that's why there's three doses. It could very well be once you get enough copper, detoxification occurring, that going higher doesn't necessarily get you more detoxifying, which we'll see. But the ceruloplasm part of the story is about copper distribution. And we know from the animal that's a little harder to achieve and therefore no bigger tutorial of

But.

Because it's a new treatment first in man, we have to we have to work through the process right and Thats why theres three doses.

<unk> once you get enough copper detoxification occurring that going higher doesn't necessarily get you more detoxifying, which we'll see but the thrill of plaza part of the story is about copper distribution and we know from the animals, that's a little harder to achieve and therefore.

I personally want to focus on the fact we are actually restoring some level of copper distribution, which to me would be the real reason why you do gene therapy, that you're not just getting rid of toxic copper, you're actually restoring copper homeostasis. And that would be the real benefit of gene therapy over everything else.

I am personally I want to focus on the fact, we are actually restoring some level of copper distribution, which to me would be the real reason why you do gene therapy that youre, not just getting rid of toxic copper you're actually restoring copper homeostasis and that would be the real benefit of gene therapy over everything else.

Great. Thank you.

Thank you and our next question comes online of Laura Shickle with Woodbush. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Laura Chico with Wedbush. Your line is open. Please go ahead.

Good afternoon, thanks for fitting me in. I just have one on Angelman. You know, assuming the best case scenario and you're advancing towards pivotal studies. And I'm wondering if you could talk about kind of on the execution side, what would be a feasible number of recruitment sites in the US? Thanks. That's a very good question.

Good afternoon, and thanks for fitting me in I just have one on angelman.

Assuming the best case scenario and youre advancing towards pivotal studies.

I'm wondering if you could talk about kind of on the execution side, what would be a feasible number of recruitment sites in the U S. Thanks.

That's a very interesting clinical ops question.

Laura. That's a question we've talked about a lot, frankly, because the usual tendency is to run with huge numbers of sites, but I would say most great studies run with a smaller number of really good sites, and that would be our focus. There are a lot of angel and patients, there are a lot of centers that have a lot of patients.

Laura.

That's a question we've talked about a lot frankly.

As usual tendency to run with huge numbers of sites, but I would say most great studies run with the smaller number of really good sites and that would be our focus there are a lot of angelman patients that a lot of centers that have a lot of patients.

if the drug data from our phase two study are as promising as we hope they will be.

If the drug data from our phase III study are as promising as we hope they will be there.

then I think the ability to enroll in study will be there. And we just need sites who can manage.

Then I think the ability to enroll a study will be there.

And we just need sides, who can manage.

intrathecal administration and the support services required for that to be able to treat patients in a fairly large study. But we haven't set a number, but I'm assuming the trial is going to be more than 100 patients just based on the size of the population.

<unk> administration and the support services required for that to be able to treat patients in a fairly large study, but we haven't set a number but I'm assuming the trial is going to be more than 100 patients just based on the size of the population.

is somewhere in there and therefore we're going to, it's going to be an international study, not just US and.

Probably less than 200.

But somewhere in there and therefore, we're going to it's going to be an international study not just U S.

And.

Our hope would be that it would be only a six-month study where we look at loading and show the difference of a clinical effect over a loading period. So I can't tell you the exact number on a number of sites. I don't think I'd venture that guess at this moment in time.

<unk>.

Our hope would be that it would be only a six month study, where we look at loading and show the difference of clinical effect over a loading period.

So I can't tell you exact number on number of sites I don't think I'd venture that guess at this moment in time, but.

If there's any issue or question you're asking about, like, are there going to be competition for patients and sites? Well, there are other programs in Ainsley, and I think there could be competition for patients, but I also point out there's a lot of Ainsley patients, right? So we think there will be enough patients to get our studies enrolled, even in the context of other programs ongoing. But more important with now is showing what our drug can do and that it's safe in Phase 2. Then everything else will come if that is successful.

If there's any issue or question, you're asking about like are there going to be competition for patients and sites.

There are other programs and Adrian I think there could be competition for patients, but I also pointed out there was a law.

What as when patients right. So we think there'll be enough patients to get our studies enrolled even in the context of other programs ongoing.

But more important with now is showing what our drug can do in that safe in phase II and then everything else will come.

If that is successful.

Very helpful. Thanks.

Thank you, and this does conclude today's question and answer session, and I would like to turn the conference back over to Joshua Haga for any further remarks.

Thank you and this does conclude today's question and answer session and I would like to turn the conference back over to Joshua Hager for any further remarks.

Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at IR at Ultragenics.com. Thanks for joining us.

Thank you. This concludes today's call. They are any additional questions. Please contact us by phone or at IR at Ultra <unk> Dot com, thanks for joining us today.

This concludes today's conference call. Thank you for participating. You may now disconnect.

This concludes today's conference call. Thank you for participating you may now disconnect.

Music

[music].

Okay.

Yes.

Okay.

[music].

The.

[music].

Good day, ladies and gentlemen.

Thank you for standing by and welcome to the fourth quarter 2021 financial results and corporate update conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you will press star 1 on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star then zero. I would now like to hand the conference over to your host today, Joshua Higgis. Sir, please go ahead. Thank you for standing by.

Thank you for standing by and welcome to the fourth quarter 2021 financial results and corporate update conference call. At this time all participants are in a listen only mode. After the speaker's presentation. There will be a question and answer session to ask a question. During the session you only press star one on your telephone please be advised that today's conference is being recorded.

If you require any further assistance. Please press Star then zero I would now like to hand, the conference over to your host today Joshua Sir. Please go ahead.

Good afternoon, and welcome to the Ultra Gen X Pharmaceuticals financial results and corporate update conference call for the fourth quarter and full year 2021, we have issued a press release detailing our financial results, which you can find on our website at <unk> Dot Com I'm Joshua <unk> Senior director of Investor Relations. Joining me on this call are <unk>.

Caucus, Chief Executive Officer, and President Camille Bedrosian, Chief Medical Officer, Eric <unk>, Chief Commercial Officer, and Mardi Dier, Chief Financial Officer.

Section on our website.

Thanks, Josh and good afternoon, everyone.

We also released with our partner genetics a clinical update on the age-win program showing positive clinical activity and no lower extremity weakness events observed.

We also released with our partner genetics, a clinical update on the Haynesville program showing positive clinical activity in lower extremity weakness events observed.

We finished 2021 in a strong financial position exceeding expectations of the performance of our commercial products. Finally, we've made good progress with our broad late-stage pipeline.

We finished 2021 and a strong financial position exceeding expectations for the performance of our commercial products.

Finally, we've made good progress with our broad late stage pipeline.

where we have initiated enrollment in three of four pivotal programs that will be ongoing this year.

Where are we and initiate enrollment in three of four pivotal program that will be ongoing this year.

Along the way, and despite the challenges presented by the COVID pandemic. We also successfully completed manufacturing technology transfer to our partner Daiichi Sankyo.

Along the way and despite the challenges presented by the Covid pandemic. We also successfully completed manufacturing technology transfer to our partner Daiichi. Thank you.

I'll let Eric, Marty, and Camille provide more details on these accomplishments later on this call.

I'll, let Eric Marty and Camille will provide more details on these accomplishments later on this call.

I do want to spend a few minutes to discuss the deal with Regeneron on the commercialization of Evkisa for the treatment of homozygous familial hypercholesterolemia, or HOFH, likes the woman. HE gunmen. Our Cookin'

I do want to spend a few minutes to discuss the deal with regeneron on the commercialization of <unk> for the treatment of homozygous familial hypercholesterolemia or HOS eight outside of the U S.

The deal also includes our exclusive right to negotiate a separate XUS agreement for their investigational antibody for fibrodysplasia, ossificans, progressive or FOP.

The deal also includes our exclusive right to negotiate a separate ex U S agreement further investigational antibody for fibro dysplasia, <unk> progress CEVA or FRP.

This deal established a strategic partnership with a leader in high quality antibody drug discovery and development.

It also enables us to both scale and leverage our commercial global commercial capabilities in commercial medical affairs and regulatory functions.

Epqis is a potent approved product with a novel treatment mechanism that strengthens our portfolio with another commercial stage, traditional biologic that targets the underlying cause of HOFH.

<unk> is a potent approved product with a novel treatment mechanism that strengthens our portfolio with another commercial stage traditional biologic that targets the underlying cause of <unk>.

This disease occurs with two copies of the familial hypercholesterolemia, causing genes are inherited one from each parent resulting in very low are absent LDL receptors on the liver.

Lead to dangerously high levels of LDL C.

Patients with HOH are at risk for premature atherosclerotic disease and severe cardiac events.

Ah patients with Asia of HR at risk for premature atherosclerotic disease.

In severe cardiac events despite.

Despite all of the studies and all the work that's been done in this disease over many years crew homozygous null patients still don't have a great treatment approved in April races to remove lipid from blood. Each single every single week is very difficult to tolerate and very cumbersome.

Epkisa targets and binds the ang PTL3, which is a protein that plays a broad role in cholesterol regulation in atherosclerosis.

As Keith had targets and binds to <unk> III, which is a protein that plays a broad role in cholesterol regulation in atherosclerosis.

in patients whose LDL receptors are not present, to direct appropriate liver uptake, if Kiese instead enables an alternative pathway by which VLDL are converted into VLDL remnants that are rapidly cleared by the liver through an alternative set of receptors.

Taking advantage of this novel mechanism significantly reduces the level of LDL cholesterol in these severe patients despite the lack of working LDL receptors.

Taking advantage of this novel mechanism are significantly reduces the level of LDL cholesterol in the severe patients. Despite the lack of working LDL receptors.

The clinical value of blocking ang PTL-3 supported by data showing that natural genetic mutations also protect patients from atherosclerotic disease, and treating LDL receptor deficient mice with an ang PTL-3 blocker does reduce angios atherosclerosis.

Clinical value of blocking <unk> III supported by data showing that natural genetic mutations also protect patients from atherosclerotic disease, and treating LDL receptor deficient mice with an <unk> blocker does reduce Andrew atherosclerosis.

And regeneron pivotal clinical program for <unk> Keith of the drug demonstrated significant improvement over standard of care with consistent 49% reduction in LDL C and the 24 week study in 65 patients with <unk> <unk> on top of all existing LDL lowering treatments.

The study also showed that treatment reduced the LDL C by 72%.

In the most severe patients with less than 2% of LDL receptor activity and that triglycerides were also reduced by 50% across study participants.

Epqisos also has a good safety profile and has been well tolerated across all study populations.

Gives us also has a good safety profile and has been well tolerated across all study population.

EVKISA is approved by the FDA and EMA for patients 12 and older. Regeneron is currently marking the treatment as EVKISA in the U.S. and we will lead its launch and commercialization in all other countries and regions including Europe , Latin America and Asia.

Of cases proved by the FDA and EMA for patients 12 and older. Regeneron is currently marketing the treatment is a key thing in the U S and we will leave its launch and commercialization of all other countries and regions, including Europe , Latin America and Asia.

We may also expand our collaboration with the Dronon to include another antibody in phase 2-3 development called FOP.

We may also expand our collaboration with Regeneron to include another antibody in phase three development called <unk>.

That license can include the same commercial rights, excluding the U.S.

That license to include the same commercial rights, excluding the U S.

FOP is an ultra-rare devastating genetic ectopic bone disease that affects approximately 1400 patients in these territories.

<unk> is an ultra rare devastating genetic topic bone disease that affects approximately 40 to 100 patients in these territories.

In patients with <unk> <unk>.

Normal bone formation occurs in soft tissue like muscles, leading to freezing of movement and difficulties in eating walking and breathing and leads to premature death by patients and their fifties.

I'll now hand the call over to Eric who will talk about the commercial team's performance last year and what is Teaming doing to launch FKISA.

I'll now hand, the call over to Erik who will talk about the commercial team's performance last year and what is teaming is doing to launch <unk>.

Thank you Emil and good afternoon, everyone.

I'll start my section discussing the commercialization team's performance in 2021, despite the impact of the Omicron variant.

I'll start my section discussing the commercialization teams performance in 2021, despite the impact of the <unk> variant.

For Chris Vida within the North American territory, we continue to see steady underlying demand from both the pediatric and adult market.

Well, Chris meter within the North American territory, we continue to see steady underlying demand from both the pediatric and adult markets in the fourth quarter. We added over 50 unique prescribers in the U S alone.

In the fourth quarter, we added over 50 unique prescribers in the US alone.

The split of pediatric and adult patients remains approximately 50-50.

A pediatric and adult patients remains approximately $50 55.

while the total number of patients on therapy continues to improve.

The total number of patients on therapy continues to increase.

We expect this split will continue shifting towards a greater portion of adults on Chrisweta as the teams are increasingly finding doctors

We expect this will continue shifting towards a greater portion of adults. When Kristina is the teams are increasingly finding doctors, who have adult patients with <unk> and tio in the community setting.

who have adult patients with XLH or TIO in the community setting.

The compliance rates remain high. In fact, four years into this launch, we continue to hear stories from patients about how much better they feel once they begin receiving therapy.

The compliance rates remain high in fact four years into this launch we continue to hear stories from patients about how much better they feel once they begin receiving therapy.

Outside of North America, demand for Chris Peter continues to gain momentum.

Outside of North America demand for Christina continues to gain momentum.

In 2021, product revenue grew 107% to $21.4 million. While there might be variability in the ordering patterns that cause some quarter to quarter fluctuations in revenue, it's clear there are strong underlying shocks and CarlAud)— telepreschooling data for programming- Hawaii Check Look at the weather wild

2021 product revenue grew one 7% to $21 $4 million, while there might be variability in the ordering patterns that cause some quarter to quarter fluctuations in revenue it's.

It's clear there is strong underlying demand for Christina.

This is a direct result of all the work the teams have been doing to educate providers.

find patients, and work with regulatory and reimbursement authorities.

Find patients and work with regulatory and reimbursement authorities.

For 2022, we expect prescriptive revenue in ultragenics territories to be between $250 and $260 million.

For 2022, we expect procedure revenue and ultra ultra gimmicks territories.

250 and $260 million.

The midpoint of this range represents 32% year-over-year growth, an impressive metric four years into a rare disease line.

The midpoint of this range represents 32% year over year growth an impressive metric for years into a rare disease launch.

Turning now to the Jovi and starting with the US launch next.

Turning now to the jewelry and starting with the U S launch metrics in the fourth quarter 2021, we added approximately 40 start forms bringing the total since launch to approximately 350 start forms.

In the fourth quarter 2021, we added approximately 20 star forms, bringing the total since launch to approximately 350 star forms.

As of the end of the fourth quarter, this has led to approximately 280 patients on reimbursed fare.

At the end of the fourth quarter. This has led to approximately 280 patients on reimbursed therapy.

Approximately 160 unique healthcare providers have written a prescription for Dijovli with many of them writing prescriptions for multiple patients.

Approximately 160 unique healthcare providers have written a prescription for <unk> with many of them writing prescriptions for multiple patients.

Outside of the US, use of Dijovvia continues through our main patient and our...

Outside of the U S use of digital continues.

Through our named patient and early access programs in Europe with Dolby growth was driven by significant increases in named patient requests in France and Italy.

In Europe , the JOBY growth is driven by significant increases in main patient requests in France In the world, the Maurer motors are divided by the additional Happier- plug-ins that the f-ascal is trying to make

We are continuing to work with regional authorities as we look to expand access for all patients who could benefit from the job.

We are continuing to work with regional authorities as we look to expand access for all patients who could benefit from digital.

late last year, the Brazilian National Health Surveillance Agency.

Late last year, the Brazilian National Health surveillance agency.

the JOGI for the treatment of both pediatric and adult patients with LC-FAOD.

<unk> for the treatment of both pediatric and adult patients with LC <unk>.

The final step is to get full reimbursement approval from Brazil's Ministry of Finance, a process we have begun working through for the last few months.

The final step is to get full reimbursement approval from Brazil's Ministry of Finance a process. We are again working through for the last few months.

I should note this will be the last quarter that.

that we provide specific launch metrics for the JOGI. We believe the 2022 guidance range of $55 to $65 million.

We provide specific launch metrics would be Joey we believe the 'twenty to 'twenty two guidance range of $55 million to $65 million.

better representation of the confidence we have in our ability to continue finding patients and getting them on reimbursed there.

Is it better representation of the confidence we have in our ability to continue finding patients and getting them on reimbursed therapy.

Now, shifting gears to the opportunity we have with EPC-TEASE.

Now shifting gears to the opportunity we have with <unk>.

which is approved for the treatment of HOFH, an inborn error of metabolism like most of our portfolios.

Which is approved for the treatment.

<unk>, an inborn error of metabolism like most of our portfolio.

These patients are typically seen by cardiovascular active specialists unequivocally released.

These patients are typically seen by cardiovascular and liquid.

HOFH is also a fairly well developed market with established diagnosis protocols, knowledgeable physicians, and a relatively high estimated rate of identified patients.

Specialists HOS age is also fairly well developed market with established diagnosis protocols knowledgeable physicians and our relatively high estimated rate of identified patients.

Across the ultragenics territories, we estimate there to be between 3,000 and 5,000 patients with HOFH.

Across the ultra genetics territories, we estimate there to be between 3005 thousand patients with H O S. H <unk>.

This program will help further establish us as a truly global commercial organization.

Program will help further establish us as a truly global commercial organization.

Initially, commercialization efforts will focus on Europe , where we estimate there to be approximately 1,600 pages.

Initially commercialization efforts will focus on Europe , where we estimate there to be approximately 16 hybrid patients.

As we modestly build on the current infrastructure that is supporting MEPS-DEB and the JOVI, we will also work to submit dossiers and begin reimbursement discussions.

As we modestly build on the current infrastructure that is supporting <unk>. We will also work to submit dossiers.

And again reimbursement discussions.

This team will also be in place to respond to requests for named patient access.

This team will also be in place to respond to requests for named patient access which could begin in 2022, given the strong interest we have seen from the Kols community.

which could begin in 2022, given the strong interest we have seen from the KOL community.

In Latin America and Canada, our commercial and medical affairs infrastructure is already well established and ready to add FPs into their portfolio.

And lastly, Latin America, and Canada are.

Our commercial and medical affairs infrastructure is already well established and ready to add Keith to their portfolios.

We have in place today the field teams and patient and prescriber support services needed to successfully launch F-KESA with very little build-out required.

We have in place today, the field teams and patient and prescriber support services needed to successfully launch <unk> with very little Buildout required.

The addition of FTS into our portfolio also sets the stage for our long-term commercial efforts as we expand into the APAC region.

The addition of FTE that to our portfolio also sets the stage for our long term commercial efforts as we expand into the APAC region.

This is a new geography for ultragenics, where we recently established a Japanese entity and have hired a general manager.

This is a new geography for <unk>, where we recently established the Japanese entity and have hired a general manager.

While F-KESER will help ultragenics to advance along its mission of being a truly global rare disease company, we should note that each of these regions are unique and have complex pricing and reimbursement processes.

While as Keith will help ultra gimmicks to advance along its mission of being a truly global rare disease company. We should note that being that each of these regions are unique and have complex pricing and reimbursement processes.

We have begun these efforts, but as you all know, it can take some time to work through these processes and see revenue from our new therapy.

Began these efforts, but as you all know it can take some time to work through these processes and see revenue from our new therapy.

Key opinion leader feedback on the program is very supportive, and the strong clinical data speak for themselves is a significant leap forward for patients with HOFH.

Key opinion leader feedback on the program is very supportive.

And the strong clinical data speak for themselves as a significant leap forward for patients with HOS H.

My colleagues and I look forward to offering Epqeza a new and compelling treatment option for patients.

My colleagues and I look forward to offering a teaser.

<unk> and compelling treatment option for patients.

In closing, I would like to reiterate just how proud I am of the team's efforts in 2021. And I look forward to 2022. We will continue to build on that.

In closing I would like to reiterate just how proud I am of the team's efforts in 2021.

And as I look forward to 2022, we will continue to build on that momentum.

With that, I'll turn the call over to Marty to share the financial results.

With that I'll turn the call over to Marty to share the financial results.

Great. Thanks Derrick.

We issued a press release earlier today that included a financial update which I will briefly summarize.

Company revenue for the 12 months ended December 31, 2021 totaled $354 million Kristina revenue and Ultra Genex territory grew to $192 6 million, including $171 2 million from the North America profit share territory and net product sales of 21.

$4 million in other regions.

Total royalty revenue related to the sales of Chris Fida in the European territory was $18.2 million. The DOLVIE revenue for the year was $39.6 million. As Eric mentioned, the ongoing strength of the launch is reflected in our 2022 guidance for the DOLVIE, which represents approximately 50% growth at the midpoint of the guidance range.

Total royalty revenue related to the sales of Christy that in the European territory with $18 2 million.

<unk> revenue for the year was $39 6 million.

Eric mentioned the ongoing strength of the line just reflected in our 2022 guidance for <unk>, which represents approximately 50% growth at the midpoint of the guidance range.

Next, W for 2021 with 16 million. As we have previously stated, we expect these revenues may modestly increase over time.

Yes, Debbie for 2021 was $16 million as we have previously previously stated we expect these revenues may modestly increase over time.

2021 revenues also included 85 million related to the tech transfer as part of our strategic manufacturing partnership with Aichi Senkyo around our PCL and HEC 293 gene therapy technology.

2021 revenues also included $85 million related to the tech transfer as part of our strategic manufacturing partnership with Daiichi Sankyo around our PCL and had 293 gene therapy technologies.

In the fourth quarter, 2021, the technology transfer activities were substantially completed and total revenue recognized under this license agreement through December 31, 2021 is $174.2 million.

In the fourth quarter 2021, the technology transfer activities are substantially completed.

And total revenue recognized under this license agreement through December 31, 2021 is $174 2 million.

Our total operating expenses for the year were $733.1 million, which includes research and development expenses of $497.2 million, SG&A expenses of $220 million, and cost of sales of $16 million. I should note this also includes a one-time expense of $50 million related to the upfront payment for the MREO license and collaboration agreement regarding the Truth of Math for OI.

Our total operating.

<unk> for the year were $733 1 million, which includes research and development expenses of 400, $497 2 million SG&A expenses of $220 million and cost of sales of $16 million.

Should note. This also includes a onetime expense of $50 million related to the upfront payment from our rail and marine our license and collaboration agreement regarding the Nab for ally.

We continue to expect our R&D spend to somewhat increase in 2022 as we support three pivotal gene therapy clinical studies, the UX 143 Phase 2-3 clinical study in OI, the Angelman Phase 1-2 study, and the Phase 1-2 study for our most advanced mRNA programs UX 053 and GSD3, and a number of other preclinical activities as we get ready to advance the next programs into the clinic.

We continue to expect our R&D spend is somewhat increase in 2022 as we support three pivotal gene therapy clinical studies. The UX one for three phase III clinical study in Hawaii. The interim in phase one two study and the phase two study for our most advance mrna program <unk> <unk> and GST three.

And a number of other preclinical activities as we get ready to advance the next programs into the clinic.

We also expect SG&A to modestly increase in 2022 as we continue to support the expansion and launches of our existing commercial products and the launch of EPCISA.

Also expect SG&A to modestly increase in 2022, as we continue to support the expansion and launches of our existing commercial products and the launch of <unk>.

For the year ended December 31st, 2021, net loss was $454 million or $6.70 per share. The net loss includes a $42.1 million decrease in the fair value of equity investment.

For the year ended December 31, 2021, net loss was $454 million or $6 70 per share.

The net loss includes a $42 $1 million decrease in the fair value of equity investments.

Net cash used in operations for the 12 months ended December 31, 2021 was $338 7 million compared to $132 2 million for the same periods in 2020.

Net cash used in the 12 month period ended December 31, 2021 included the $50 million upfront payment for the closing Thats been L'oreal agreement.

This compared to the net cash used in the same period of 2020 that included approximately $155 million of operating cash received from Daiichi Senkyou related to the collaboration and license agreement.

This compared to the net cash used in the same period of 2020 that included approximately $155 million of operating cash received from Daiichi. Thank you related to the collaboration and license agreement.

Now I'll turn the call over to Camille to touch on some of our clinical programs.

Now I'll turn the call over to Camille to touch on some of our clinical program.

Thank you Marty and I too wish everyone. A good afternoon, and my section I will briefly provide status updates on our six clinical stage programs before turning back the call to Amazon.

Starting with the three gene therapy programs.

DTX401 for the treatment of glycogen storage disease type 1A or GSD1A is currently dosing patients in the randomized placebo controlled phase 3 study.

<unk> for the treatment of glycogen storage disease type <unk> or <unk> is currently dosing patients in the randomized placebo controlled phase III study.

DTX301 for the treatment of ornithine transcarbamylase, or OTC, deficiency is in the final stages of study startup. We anticipate the first patients will enter the four to eight week baseline screening period in the first half of 2022, after which they will be dosed in the phase three randomized placebo controlled study.

Gtx 301 for the treatment of ornithine <unk> or OTC deficiency is in the final stages of study start up we.

UX701 for the treatment of Wilson disease is currently enrolling patients in a seamless phase 1, 2, 3 randomized placebo controlled study.

<unk> 701 for the treatment of Wilson disease is currently enrolling patients in our seamless phase 123 randomized placebo controlled study.

Outside of Gene therapy, you X 143, or <unk>, an anti <unk> antibody, we will begin enrollment in the first half of 2022 and the seamless phase III study for pediatric and young adult patients with osteogenesis imperfecta.

Gtx 102, the ASO in development with our collaborator genetics for patients with Angelman syndrome continues to enroll and dose patients under the amended phase one two protocol and the UK, Canada and the U S with no reported lower extremity weakness.

Cohorts four and five in the UK and Canada following DSMB support have expanded, adding an additional eight patients to this protocol.

Cohorts four and five in the UK and Canada. Following DSM support have expanded adding an additional eight patients to this protocol.

The initial assessments have shown early signs of clinical activity.

The initial assessments has shown early signs of clinical activity.

We look forward to providing an update on this program in mid 2022.

UX053, our first mRNA for the treatment of glycogen storage disease type 3, is currently dosing patients in the single ascending dose arm of the phase 1, 2 study.

<unk> <unk> three our first mrna for the treatment of glycogen storage disease type III is currently dosing patients in the single ascending dose arm of the phase one two study.

Preliminary data from that arm, as well as initiation of the repeat dosing phase of the study, are anticipated in the second half of this year.

Preliminary data from that arm as well as initiation of the repeat dosing phase of the study are anticipated in the second half of this year.

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

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

Thank you, Camille. Before we close out, I'll provide a quick reminder of the key upcoming milestones for the company.

Thank you Camille before we close out I'll provide a quick reminder of the key upcoming milestones for the company.

For Gtx, one or two in Angelman will provide an update in mid 2022 on cohorts four and five in the Canada and UK arm of the study.

As well as available safety and efficacy data from the patients treated in the U S.

For UX 143 in Osteogenesis and Perfecta, we'll begin dosing in the pivotal phase 2-3 study in Pediatrics in the first half of the year.

For U S $143, two jensen perfect that will begin dosing in the pivotal phase III study in pediatrics in the first half of the year.

In the 2nd half of the year, we expect to provide an update on the dose strategy we have selected for the phase 3 portion and initiate a supportive study in children under 5 years old.

In the second half of the year, we expect to provide an update on the dose strategy. We have selected for the phase III portion of initiate a supportive study in children under five years old.

For UX053 in the second half of the year, we expect to share single dose data from the first part of Phase I-II study and to initiate the repeat dosing stage.

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

In 2021, we've made meaningful steps in building a strong financial position bolstering our commercial portfolio advancing our clinical programs and completing the tech transfer our gene therapy manufacturing technology or ahead of schedule in 2022, and we look forward to building on this and sharing updates with you.

With that, let's move on to your questions operator. Please provide the Q&A.

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

Thank you. If you have a question at this time, please press star then 1 on your touch tone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. We ask that you please limit yourself to 1 question or 1 follow up. Our first question comes from the line of Yiko Nakamoto with Citigroup. Your line is open. Please go ahead.

Our first question comes from the line of <unk> <unk> with Citigroup. Your line is open. Please go ahead.

Great, thank you very much for taking the questions. I just had a question with respect to your planning for the pivotal trial for Hingelman. Presumably you're going to do a randomized placebo controlled trial. And so my question is assuming you see a mean CGI, I guess, increase in line with the two and a half that you've observed so far in the phase one, two.

Great. Thank you very much for taking the question I just had a question with respect to your plan and for the pivotal trial for Haynesville minimums, presumably you are going to do a randomized placebo controlled trial and so my question is assuming you see EMEA and CGI, Inc.

The increase in line with the two five that you've observed so far in the phase one two how are we thinking about the separation from placebo given the natural history and Angelman.

How are you thinking about the separation from placebo, given the natural history on Angelman's, where clinicians have actually observed slow gains in function over time? For instance, there's a 2020 publication in the Journal of Autism and Developmental Disorders that makes this point quite nicely. Thank you.

Clinicians have actually observed slow gains and it function over time.

Since the 2020 and publication in the journal of autism and developmental disorders that makes this point.

<unk> quite nicely. Thank you.

Thank you, Igual. I think one thing about angeman is though there may be some small gains over time, the gains are pretty modest compared to the kind of change observed in the trial. So I have no question if we can achieve the efficacy we've seen before in our phase 3.

Thank you.

One thing about <unk> is though there may be some small gains over time, the gains are pretty modest compared to the kind of change observed in the trial. So I have no question. If we can achieve the efficacy we've seen before in our phase III that we'll be able to distinguish that from placebo Im really no concern at all the CGI is a tool is wanted.

<unk> to measuring disease, but it has a more subjective approach depending on the opinion of the investigator. We also are certainly going to use underlying instruments.

that we used before, such as Bailey's and others, that are specific measures of particular function, which we will be studying in our phase two study currently with genetics, which will allow us to understand the magnitude of effect and understand separation. And I have no doubt, given the effect we've seen before, that we can design a study that will have appropriate endpoints and capture what was, in our view, a very profound effect on development in this disease.

We used before to the bally's and others that are specific measures of particular function, which we will be studying in our phase two studies currently with genetics, and which will allow us to understand the magnitude of effect and understand separation and I have no doubt given the fact, we've seen before that we can design a study that will have appropriate.

The endpoints and Meg and capture what was in our view a very profound effect on development in this disease right now we need to get our optimize our dosing, which we're working on and figure out. This we'll figure out the magnitude of these effects and come up with a design for the study, whether it's CGI dependent or whether it's based on other.

Okay, thank you. That's super helpful. And then just to follow up on another topic regarding the Regeneron deal, obviously this was very interesting as you usually see the smaller company licensed to the larger firm to commercialize an asset, but obviously the reverse happened here. So the question is, could we see more transactions following what happened with stays out.

Okay. Thank you.

Helpful. And then just a follow up on another topic regarding the regeneron deal.

Obviously this was very interesting as you usually see the smaller company license to the larger pharma to commercialize the asset, but obviously the reverse happened here. So the question is could we see more transactions following what happened with <unk>.

Or was this more of a one off situation that presented itself will for general thanks.

Yes, well I think we just are a big company and how we act and behave so that's what's going on here now, but regeneron is a great company, but they haven't built a global commercial.

capability, especially in the rare space. They were appreciative of what we had and felt the best thing for their product. And they really cared about these patients and wanted to get good care. And they said, we want you guys to handle this product because they have confidence in our belief to take care of business and do it well. So if there's anything that's our reputation for taking care of people correctly that draw us together, it is a true problem.

Capability, especially in the rare space.

We're appreciative of what we had in and felt the best thing for their product and they really care about these patient wanted to get good care and they said we want you guys to handle this product because we have confidence our belief to take care of business and do it well. So if there is anything as our reputation for taking care of people correctly correctly that draw together. It is a two product deal.

Look, we're pretty full of the fizzy and pipeline right now. So right now we're not expecting to do many deals on other commercial deals, but...

Look we are we're pretty full with busy in pipeline right now so right now we're not expecting to do.

Many deals on other commercial deals, but in our view, we want to be selective.

In our view, we want to be selective. We want to pick products that we want to work on that we're proud of, that we think really change care and are important in order to get us to take our precious people's time and put them on an effort. And if KISA, we think, will be a change in standard of care, and we think Gorizmab has the potential to be life changing for FOP. So we're excited about both of those. And right now, we'll stick to just keeping those going, and we won't think about what else could be. We'll wait.

To pick products that we want to work on that we're proud of that we think really change care in our part important.

In order to get us to take our precious people time and put them on an effort in the pizza. We think is will.

It will be a change in standard of care and we think <unk> has the potential to be life changing for FRP. So we're excited about both of those and right now we'll stick to just keeping those going in we won't think about what else could be.

Okay, appreciate it. Thank you.

A wait and see if it comes.

Okay. Appreciate it thank you.

Thank you and our next question comes from the line of Gina Wang with Barclays. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Gena Wang with Barclays. Your line is open. Please go ahead.

Thank you for taking my questions. I also have one question regarding endermen. So, I mean, in the early January update, you said, you know, the sign of improvement in terms of CGI score.

Thank you for taking my questions I also have one question regarding Ann Julian.

So emil.

Early generally update you said.

Sign of improvement in terms of CGI score so but did you continue to see that trend if you can be.

Be a little bit more quantify regarding the score improvement in the past you mentioned like two score improvement in two out of five domains did that meet that criteria.

Then second part is mid this year can you lay out specifically what kind of data are we expecting to see from the 12 patients. For example, the first two patients from each cohort the loading dose after initial loading dose what additional data we could see and also for the remaining patient.

We could see and will you have a definitive answer by mid this year that you would know which dose to move forward.

The pivotal study.

Very good. So thank you Gina for Angelman. What we said was and we'll just reiterate.

Okay. Good so thank you gena for Angelman.

What we said was and we'll just reiterate is that.

We had improvements in clinical activity, that is their CGI scores for the domains were improving. But in the lower dose cohort we had said that they hadn't achieved plus two in more than two domains, therefore the patients escalated to the next dose level.

We had we.

We had improvements in connectivity that is their CGI scores for the domains where improving.

But in the lower dose cohort, we had said that they hadn't achieved plus two and more than two domains. Therefore, the patients escalate to the next dose level.

In cohort five, the older patients, that DMC has met and also allowed the expansion to cohort five, the additional four patients in that cohort.

And cohort five the older patients that DMC has met and also allows the expansion of to the cohort five additional.

And those patients also escalated. That is, they were seeing improvements, but not too dilliant, too plus. So we're at the beginning of the titration. We still want to get in the clinic, get started. We're seeing activity. We're not seeing any lower extremity issues right now. So we're encouraged. They'll continue to dose and titrate as we move forward with those 12 patients. So that's a big part of that.

For patient in that cohort and those patients are also escalated that as they they were seeing improvements, but not to delay two plus so we're at the beginning of the titration. We wanted to get in the clinic get started we're seeing activity, we're not seeing any lower extremity issues right. Now. So we are encouraged they will continue to dose and titrated as we can.

Move forward with those 12 patients so thats kind of where we're at we Havent put out specific Florida, but we said if they had two domains of two plus they wouldn't titrate further that would be considered getting to the level of efficacy. We saw before so we're encouraged but we're continuing to move forward with dosing and titration.

Now, what kind of data will we see? Well, we're talking about mid-year.

Now what kind of data will we see what we're talking about mid year.

That that data would be expectation would be that we would see data from the first cohort four and cohort five.

Gotten their doses and evaluated at.

De 128, which includes now a whole series of endpoints not just CGI and domain, but will include the bally's expressive and language scores Vineland scores fleet evaluations.

And as well as the.

was one of my behavior evaluations. So we would have a number of endpoints that we'd be supporting. Those endpoints would come from both patients or families.

I was wondering behavior evaluation. So we would be have a number of endpoints that we'll be supporting those endpoints would come from both.

Patients or families.

the investigator or a psychologist. So there's three different types of evaluators. So we think we can look at the synchrony between different evaluators and how they're looking at these with different endpoints. We hope this will be a robust assessment of how the drug's doing.

So, with regard to where we are, the point of this program is to kind of get dosing and titrate dose until we see sufficient efficacy that we would separate from placebo in a trial and be a substantial clinical benefit to patients. And we'll see at that point, we look at that data, if we have achieved that level.

So with regard to where we are the point of this program is to kind of get dosing and titrate dose until we see sufficient efficacy that we would separate from placebo trial and be a substantial clinical benefit to patients and we will see at that point, we look at that data. If we're if we achieve that level.

If we are close to it or at that level, we expect that we would expand the cohort and actually add more patients beginning at the new dose level that we've established and move forward. Now you asked how are we going to know when we got to the dose? I'm guessing by mid-year we'll have a sense for the dose, but it could be that the expansion cohort will help.

I'm guessing by midyear, we'll have a sense for the dose, but it could be the expansion cohort will help <unk>.

Identify or verify that higher level. The idea is to try to tune up the advocacy and manage within what we consider safe dosing range.

Identifier verify that higher level. The idea is to try to tune up the efficacy and manage within what we've considered safe dosing range.

That would allow us to see results later in the year regarding that dose.

That would allow us to see results later in the year regarding that dose and it could be that we deal with a young does an older dose or it could be something else. We do but the idea is we're going to learn about how to dose and get an idea of what the optimal dose ranges, but we're really encouraged so far that we're not seeing anything at all with the the risk.

And it could be that we deal with a young dose, an older dose, or it could be something else we do. But the idea is we're going to learn about how to dose and get an idea of what the optimal dose range is. But we're really encouraged so far that we're not seeing anything at all with the risk of a lower extremity event. And so we're encouraged we're seeing activity and we think we just need to work into the deeper in the therapeutic range as we move forward. So we're excited about potential with Angelman.

Lower extremity event.

So we're encouraged we're seeing activity and we think we just need to work into the deeper in the therapeutic range as we move forward. So we're excited about potential with instruments.

Great. Thank you very much.

Thank you and our next question comes from the line of Casino.

Hamed with Bank of America. Your line is open. Please go ahead. Hey guys................

And Ed with Bank of America. Your line is open. Please go ahead.

Hey, guys. Thank you for taking my questions.

Just one point of clarification for Angelman's. Emil, can you just remind us about whether or not you will be able to redose those original five patients that you had on drugs? If you don't know yet, is that gonna be part of the discussion with the agency? What would you need if it's not been decided yet to get them comfortable with redosing? And then secondly, for Epiza, what would you need?

Just.

One point of clarification for Angelman.

Can you just remind us about whether or not you will be able to re dose those original five patients that you had on drug.

If you don't know yet is that going to be part of the discussion with the agency and what would you need if it has not been decided yet to get them comfortable with re dosing and then secondly for F. Kiva.

Can you talk about where, you know, in a little bit more detail, the synergies are between the products that you currently market and what you would need to build out to market at HOFH.

Can you talk about where.

More detail the synergies are between the products that you currently market and what you would need to build out to market HOS H. Thanks.

Very good, thanks, Tazeen. So for Angel Men, we're obviously very interested in redosing those original five. So are those families because they've seen so much and to have that pulled away has, of course, been tough for them. And so they're anxiously waiting. Our belief is we need two things in order to go back to the agency.

Very good thanks, <unk> so for Angelman, we're obviously very interested in re dosing those original five so are those families because they had seen so much.

Have that pulled away has of course been tough for them until they are anxiously waiting our belief is we need two things in order to go back to the agency.

We want to collect data from the XUS program that's ongoing right now to help look at the dose and retina integration method to help verify it.

We want to collect data from the ex U S program is gone going right now to help look at the dosing regiments deterioration method.

and just to show that we can dose safely. The second thing...

Verify it.

And just to show that we can dose safely.

Second thing.

Because we are doing some evaluations on Hematological response to those things, which will show that there is no hematological issues at all which I think was part of the original concern on re dosing with those two elements in hand, we would expect to go to the agency in this this.

This year middle of this year.

and would seek a plan to re-dose those patients and get them back on treatment. And we'd hope that that also eventually gets essentially the world program, the ex-US programs aligned in terms of dosing and administration. So we think we want to have some of the data from these next set of patients as well as this additional evaluation of those five in order to get to the next step on re-dosing.

And would seek a plan to re doses patients to get them back on treatment and.

And we would hope with that also da Vinci really get essentially the world program. The U S. Ex U S programs align in terms of dosing and administration.

So we think we want to have some of the data from these next set of patients as well as with additional evaluation of those five in order to get to the next step on re dosing.

So on <unk> Keith.

Our centers of excellence are defined by the government.

And therefore, it really is a very easy orphan model to go out and with a small number of field people manage a limited number of centers. So we're very comfortable that the basic inner workings of supply medical affairs as well as reimbursement are things that we can use and we will have.

A very limited number of growth and people that would go to those centers.

The thing that will also happen is that the thing that will also happen is that EF-KISA will enable us to go to more countries in Europe , which will expand our footprint a bit, which will allow us to gain revenue from more countries than we currently are. And so I think that's where the, we will actually gain benefit from EF-KISA, which will set us up for the rest of the other programs we have.

The thing that will also happen as of Keith will enable us to go to more countries in Europe , which will expand our footprint a bit which will allow us to gain revenue from more countries.

We currently are and so I think that's where the.

We actually gained benefit from <unk>, which will set us up for the rest of the other programs we have.

with the work we will do. So we're comfortable that we can leverage. We'll we some growth, but we think we'll get a lot of benefit from the team we have who can move on to working at KISA.

With the work we will do so we're comfortable that we can leverage.

Some growth, but we think we'll get a lot of benefit from the team we have who can move on to working of chiesa.

Remember, F-KISA and HOFH is still a lipid metabolism disorder. And while there may be sometimes different doctors involved, it is fundamentally a genetic metabolism disorder and our team is well capable of doing it. The other thing I'll point out is because it's such a common, really well-known disease area, it's not as hard as some rare disease areas, right? Everyone knows about LDL. Everyone knows about diagnosis of this disease. It's not like a mysterious disease, which might be more challenging.

Remember if Keith.

<unk> is still a lipid metabolism to order because disorder and while there may be sometimes different doctors involved it is fundamentally a genetic metabolism disorder and our teams well capable of doing it. The other thing I'll point out is because it's such a common welling really well known disease area, it's not as hard as some rare disease areas right everyone knows about LDL.

Everyone knows about diagnosis of this disease is not like a mysterious disease, which might be more challenging here.

Here, the patients are known. They already go to places.

Here is the patients are known they already go to places. The challenge is just finding them get them on drug in the major centers that won't take a lot of people will be will be efficient in how we setup commercialize up chiesa.

challenge is just find them, get them on drug, and if they're at the major centers it won't take a lot of people and we'll be sufficient in how we set up and commercialize IPCISA.

Okay. Thank you.

Thank you and our next question comes from the line of Corey Kazimov with JP Morgan. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Cory CASM off with Jpmorgan. Your line is open. Please go ahead.

Hey, good afternoon, guys. Thanks for taking my question. Two for me as well. I guess first, just to follow up on the Efkiza topic, can you just talk a little bit more about the anticipated cadence of countries coming online here? Do Canada and Latin potentially contribute in 22, or should we think about these as more of a...

of 2023. And then to change it from Angelman, can you talk about what we might learn?

2023, and then to.

To change it from Angelman can you talk about what we might learn from the phase II dosing update source of truth, a mab or UX $1 43 in the second half of this year.

Do we get like a full on safety and efficacy update around the various doses or is it just more of like the dose you chose and the plan for phase III. Thank you.

Okay very good so on a chiesa.

There is a sequence that usually people worked through in country by country and I, probably wouldn't go through that at this moment, but obviously in Germany. You can launch we're quickly but other countries like France, Italy have a process, we have to work through and we're going to work through the filings and timing of these things to manage the pricing process to get through it and to try to achieve.

the pricing process to get through it and to try to achieve consistent pricing across the region. So I won't go through it right now, but 2022 will be spent primarily filing reimbursement and beginning the process of getting reimbursement in these countries.

<unk> consistent pricing across the region.

So I won't go through it right now, but 2022 will be spent primarily filing reimbursement and beginning the process of getting reimbursement in these countries.

And ultimately Germany at some point is the one country you can launch sooner and of course that would be something we would do on our plan with regard to Canada and Latam.

This still requires filing an approval. So it's obviously not going to be a big revenue generator in this year.

Canada, LATAM is also right now launching Joel Jolby and LATAM, Crispida is still in the beginning of its growth. So they have plenty to do there, but EPCISA will fall in after that. But this year will be more about driving Europe . Again, we'll get the filings in for the rest of Western World for EPCISA.

Canada and Latam is also right now is to also launching <unk>.

And in Latam could feed is still.

In the beginning of its growth. So they will have plenty to do there, but Keith will fall and after that but this year will be more about driving Europe again, we will get the filings and for the rest of the world for a pizza.

Now for the next one, was it both UX 143 and Angermann? Was it both or just UX 143? Yeah, I kept hearing Angermann all the time. Maybe I'm kind of beaming it now. So UX 143, look it's a...

Now for.

The next one was at both <unk> was it both or just esport form 43, so one PRT.

Yes, Okay I kept hearing easement all the time, maybe in the kind of premium.

Okay.

<unk> three <unk>.

It's a pretty simple story.

They already proved that 20 mckeel works quite well, right? We know that already.

They are already proved 20 kilo works quite well right, we know that already.

We're now going to young kids, so we're going to test a higher dose.

end that dose and kind of compare. And the purpose is really fine-tuning it. It's not like we don't know. We know the dose is probably 20. The question is do you need to go hire some little kids? That's all. And so what we're going to do is try to figure out is maybe the five-year-old needs to be on 40 and the old ones are on 20, you know, and maybe somewhere in between. So we're going to kind of look for how do we assess drug distribution.

And that dose and kind of compare and the purpose is really fine tuning is it's not like we don't know we know the dose is probably 20 of the question is do you need to go higher for intermodal.

That's all and so we're going to do is try to figure out as maybe the five year old <unk> 40, and the old ones are in 'twenty and maybe somewhere in between so we're going to kind of look for how do we assess drug distribution pharmacodynamic effect at different ages and doses entrust created dosing algorithm I think it would lessen that OS is the dosing out.

at different ages and doses and just create a dosing algorithm. I think it would less as a dose as a dosing algorithm to how to optimize for age. And based on P1P which in a actualynagirls.com we don't have in the chat box owners, but those who've been mid poly

For them to how to optimize for age and based on <unk>, which in our hand showed or at least in the hands of the study excuse me have showed a really good correlation. So that's kind of what we're expecting we'd put out a significant data to say here's what we're doing in our dosing algorithm will talk at a high level about dosing, we probably would not provide.

showed, at least in the hands of the study, excuse me, has showed a really good correlation. So that's kind of what we're...

expecting. We put out a significant amount of data to say here's what we're doing in our dosing algorithm.

<unk>, great detailed data because it's in the middle of a blinded study and so we will have some restrictions on how much detail, we can provide but it should be enough to say.

drugs working, we figured out how we're gonna dose, and then we're heading to phase three. And I think that would be an important update for the program. Okay.

Drugs working we figure out how we're going to dose and that we're heading into phase III and I think that would be an important update program.

Okay. That's very helpful. Thank you.

Thank you and our next question comes from the line of Chris Raymond with Piper Sandler. Your line is open. Please go ahead.

Thanks.

Got a couple of non Angelman questions. If that's okay.

Maybe just the first one.

Speaking of the Regeneron deal, I think you've highlighted Amyl before. The second drug in that, potentially second drug is garitosumab.

Speaking of the Regeneron deal I think you've highlighted a mold before the second drug in that potential.

Potential potentially second drug is keratose mab.

You know, just Regeneron, I guess, ran into some issues with when they were developing some fatal SAEs at the end of, I guess it was 2020, and they kind of went silent on it. But I guess it's not clear, I guess, that these deaths were treatment related.

Regeneron I guess ran into some issues with when they were developing with some fatal.

At the end of I guess, it was 2020 and they kind of went silent on it but just to get into this it's not clear I guess that these deaths were treatment related.

But there still seems to be a safety signal. Maybe just curious, if you could maybe expand on what you see with that molecule, Emil, in terms of the path forward.

But theres still seems to be a safety signal maybe just curious if you could maybe expand on what you see with that molecule a mall in terms of the path forward.

And then just maybe a follow up on Corey's question on Citrusimab.

And then.

Just maybe a follow up on <unk> question, So curious I mab.

I think I've heard you say in the past, you framed this as maybe an opportunity that when you compare it to XLH, that the demand might even be greater for treatment. Can you just high-level, maybe expand on that a little bit in terms of the market opportunity that you see and just kind of thinking about that as setting up as a big catalyst in the next year, or end of this year, I guess?

I think I've heard you say in the past you frame this as maybe an opportunity.

<unk> when you compare it to XL H that.

But the demand might even be greater for treatment can you just.

High level, maybe expand on that a little bit in terms of the market opportunity that you see just kind of thinking about that as a <unk>.

Setting up as a big catalyst in the next year or end of this year I guess sure.

So I'm greeted now, but obviously I need to defer to Regeneron on details of their program. What I can say is we evaluated and the depth they had in their study, some very advanced patients who have scores were very advanced.

So Great example, obviously I need to defer to regeneron and details of their program, but what I can say is we evaluated and the depth. They have in their studies some very advanced patients who have a scores were very advanced.

We look at all that and our conclusion is the drug is not the cause of those, that they are just very sick people and have advanced disease. And that is why we're comfortable with what is going on.

We look at all of that our conclusion is the drug is not the cause of those they are just very sick people and have advanced disease and that is why we're comfortable with what is going on the drug may have events, we're not going to talk through them, all but what I can say to you is its effect on diseases. So profound disease. So <unk>.

The drug may have events, we're not going to talk through them all, but what I can say to you is its effect.

on disease is so profound, disease so horrible, that we feel confident it's a drug that should get approved.

Horrible that we feel confidence that drug that should get approved.

Right now, Gorgeneron is doing their work and developing the development strategy and I would refer to them on that development strategy. We're confident there's a good product in there from our look at things.

Right now to Regeneron is doing their work on developing the development strategy and I would defer to them on that development strategy, but we're confident there is a good product in there from our looked at things.

Purchase the truth Mab.

The OI patient population that can be treated as both type 1

The Oi patient population that can be treated us both type ones as well as type Threes type force now if you look at the type of type ones have fractures and there can be a variable degree some people have occasional fractures and have.

as well as Type 3s and Type 4s. Now, if you look at the types, Type 1s have fractures and there can be a variable degree. Some people have occasional fractures, some have Not local locked. micro-

you know, more than occasional, more significant. So it's some fraction of those patients are really having more issues. Type 3 to type 4 are physically more devastated patients and their bodies are disintegrating. Those patients are far more advanced and impaired than let's say a child with XLAH, right? These kids end up in wheelchairs significantly compared.

More more than occasional more significant so some fraction of those patients are really having more issues type III type wars are physically more devastated patients and their bodies are disintegrating in those patients.

Far more advanced in impaired than let's say a child with <unk> trial. These are kids ended up in wheelchairs significantly compared kids right. They are devastated not just crooked legs. We're talking about then bodies right. So there's no doubt the tier three and four are horrible and even with this phosphonate to whatever it is being done with them now is nowhere.

kids, right? They are devastated, not just crooked legs. We're talking about

bent bodies, right? So there's no doubt that type 3 and 4 are horrible and even with bisphosphonates, whatever is being done with them now is nowhere close to adequate treatment. So we think there's a very high need in the OI population.

Close to adequate treatment. So we think theres, a very high unmet need in the <unk> I'm sorry in the in the Oi population.

And we've been looking the last few years for something better. And what we've been impressed with is that they're among anabolic agents, antiskerostin.

And we've been looking glass year for something better and.

What we've been impressed with is that they are among anabolic agents anti score Austin.

Is very potent and has the biology sufficient to basically normalize the strength of the bond in models and the drug in their study showed dramatic improvement in bone.

Density in the lumbar spine, which is one of the places the type three and four patients disintegrate their spines essentially collapse and disintegrated.

this drug had 8 to 10 percent bone marrow density improvement in just one year, which is more than double any other anabolic age in lumbar spine. So we think that the potency in improving lumbar spine, for example, for young patients would be profound and the strength then could change our future from one of constantly broken bones and declining function to one of stabilized and improved growth and function. So we're...

This drug had 8% to 10% Beaumont density improvement in just one year, which is more than double any other anabolic agent in lumbar spine. So we think that the potency and improving lumbar spine for example for our young patients would be profound and the strength then achieved could could change our future from one of constantly broken bones of declining function to one have stabilized.

And proof growth and function. So we are we believe given that severity unmet need there'll be a big driver, but on top of that when you talk to kols, especially the larger kols. They generally a 50% to 100% more <unk> patients and <unk> patients in their clinic.

And so the 60000 prevalent population realized probably could be higher than that we think theres about 50000 escalation that same population, but it could very well be there is more than <unk> by a significant amount and thats why we add that on with a high unmet need we think it's a population needing our help meeting.

A new drug.

And we're in good position to get there with this one.

Great. Thank you very much.

Thank you and our next question comes from a line of yarn we're with Cowan. Your line is open. Please go ahead.

Thank you and our next question comes from the line of yarn Werber with Cowen. Your line is open. Please go ahead.

Hi, this is Brendan on free around. Thanks for taking the question guys. Just one quick one on Chris feeder understand the rest of world and person can be a bit choppy. But obviously, it was a pretty impressive quarter quarter jump in North America. I just want to see maybe what drove that in Q4 and how we should think about it in context, maybe moving forward this year.

Hi, This is brendon on for you Ron Thanks for taking the questions guys.

One quick one on Chris' Vita I understand the rest of world in person can be a bit choppy, but obviously it was a pretty impressive quarter over quarter jump in North America I just wanted to see maybe what drove that in Q4, and how we should think about it in context and maybe going forward. This year.

And then just a quick one on the GSD three readout in the second half.

What kind of data can we may be expecting from how many patients are you expecting by then I wasn't sure. If you said, we'd get repeat dosing data or if it will just be the stat patients. Thanks very much.

Thank you Bren I'll, let Eric handle the crispy the quarter on quarter.

number question and then Camille can handle GSD3 patient briefly.

Question, and then Camille can handle GSD three patient briefly.

Briefly thank you.

Yeah, we had a strong fourth quarter.

Yes.

We had a strong fourth quarter.

you know, it surged following a summer lull, which was driven by the Delta virus, where there was a lot of lower activity in the mid-year with patient volumes going into office.

If serge following.

Summer lull, which was driven by the Delta virus, where there was a lot of lower activity in the mid year with patient volumes going into offices.

So we saw a surge at the latter part of the year as we rebounded coming out of that Delta variant.

So we saw a surge at the at the latter part of the year.

We rebounded coming out of that.

Dr. Gary.

Oh, great. Thanks for the question about <unk> program, Yes, we will have data on our open label single ascending dose portion of the study in the second half of 2022.

Approximately eight to 10 patients of data.

As the name suggests, the doses will be escalated.

As the name suggests that the doses will be escalated.

after by cohort by cohort. And so we'll have information first and foremost on the safety, as well as some additional pharmacodynamic and initial clinical activity.

Data until that portion and completed but we'll certainly give you an update on where that portion stance in the second half of care as well.

Okay, great. Thank you.

Thank you. And our next question comes online of Maury Raycroft with Jeffries. Your line is open. Please go ahead.

Okay.

Thank you and our next question comes from the line of Maury Raycroft with Jefferies. Your line is open. Please go ahead.

Hi, Congrats on the progress and thanks for taking my questions.

I was going to ask one on the Angelman.

I'm wondering what the cadence of enrollment could look like in the United States.

Many patients do you plan on enrolling in the U S. At two Megs and where you have the ability to adapt dosing or expand the study in the U S. During the four month timeframe I guess could there be a use dosing update before year mid year data update.

Yeah, very good. The patients are essentially, I think they're essentially enrolled now, right? Clerk's enrolled. So we're enrolled. The 4 patients that were planned for 2MIG, so that's already there. And then...

Yeah very good.

Patients are essentially I think they are essentially enrolled in our <unk>.

So were were enrolled before patients that were planned for two Mig so that's already there and then.

We're playing is we're letting them go and get started and was an agreement with FDA just to get started. I think our plan was to take enough data from our ex-US to come back to the agency. And look through what we can do to update the US program. I would expect that somewhere toward the middle of the year. I don't know that by the update we would have changed the FDA.

We're playing we're letting them go and get started and with an agreement of the FDA rules to get started I think our plan was to take enough data from our ex U S to come back to the agency.

And look through what we can do to update the U S program I would expect that somewhere towards the middle of the year I don't know that by the update we would have changed the FDA.

protocol for the US yet, but we're planning to try to get as much data from the current set of patients so that we go back to the agency with a very crisp single package and get their agreement. So once we have the other safety information in that, we hope to go back and...

The protocol for the U S yet, but we're planning to try to get as much data from the current set of patients. So that we go back to the agency with a very crisp single.

Package and get their agreement. So once we have the other safety information that we hope to go back in.

And align the U S protocol with the ex U S. We would have to deal with patients who are on two Mig.

By that point, they will probably have their doses completed, but we would probably expect to enroll them in.

As participants in the next in the cohort of the expanded protocol that we're doing so.

We can't tell you exactly, but we're going to try to get to that certainly mid-year.

We can't tell you exactly but we're going to try to get to that certainly mid year.

Got it. That's helpful. And then I just had a quick question on the FOP option with Regeneron. I guess for a PISA, I'm wondering if there are near term obligations with launches that may factor into negotiations related to the exclusive FOP option.

Got it that's helpful. And then I just had a quick question on <unk>.

Option with Regeneron I guess.

<unk>.

I'm wondering if there are near term obligations with launches that may factor into negotiations related to the exclusive <unk> option.

Well, the two things are not really tied to each other. There are certainly, in our agreement with on efKISA, we'll have.

Well the two two things are not really tied to each other there are certainly in our agreement with <unk> that will have.

aspects of performance that we need to execute on and that's all agreed to, but the option doesn't depend on those. It's just what our requirement is. The option will depend on at point in time, it will provide information that they have and what their development plan is and we'll have the ability to opt in and then start to share some of the development costs for the greatest map. So, the two things are not related to each other and at this point.

Aspects of performance that we need to execute on and Thats all agreed to but the option doesn't depend on those it just put a requirement in the option will depend on as point in time, we will provide information that they have and what the development plan is and we will have.

The ability to opt in and then start to share some of the development costs for a period of map.

So the two things are not related to each other.

At this point.

Got it okay. Thanks for taking my questions.

Thank you and our next question comes from the line of Degan Haw with Steeples. Your line is open, please go ahead.

Thank you and our next question comes from the line of Dan.

With Stifel. Your line is open. Please go ahead.

Great. Good afternoon. Thanks for taking our questions. I'll also stay away from Angelman tonight. One, just on FQE's...

Great. Good afternoon, thanks for taking our questions.

So stay away from Angelman Tonight, one just on his keys.

It seems to be more commercially driven but I was wondering if I could get your take on <unk> III targeting gene editing approach and whether or not you consider that before you went with <unk>.

And then secondly on <unk>.

I guess, can you remind us in terms of how you're thinking powering wise that you're going after fracture versus the bone density that was measured in the asteroid study? Thank you.

I guess can you remind us in terms of how youre thinking empowering wise.

And after fracture versus the bone density that was measured in the asteroid study. Thank you.

Okay. So in the commercial side...

Okay.

So in the commercial side.

There's obviously other ways to talk out of ANJ-PTL3, but the antibodies in hand is very safe, works well.

There is obviously other ways to target <unk> three but the antibodies in hand is very safe worked well.

and genetic knockout strategies have just submitted the very first few patients.

And gene editing knockout strategy.

Yes.

which is very exciting, but to me is going to take years to get through.

The very first few patients.

Which is very exciting to me is going to take years to get through.

The goal people have in trying to do this is certainly not treating HSH and gene editing. But right now we're watching the gene editing field. We're a company that likes to take advantage of platforms, but not have to develop them ourselves. So, in our view, what we needed was not another early stage program to experiment with, but a product that we could sell that worked. And down the road, if your point is, well, could something replace

The goal of people have been trying to do this is certainly not treating HSH in gene editing, where right now we're watching the gene editing field.

We are a company that likes to take advantage of platform, but <unk> have to develop them ourselves. So in our view what we needed was not another early stage program to experiment with a product that we could sell that worked in down the road. If your point is well could something were place.

EPCISA for DANG PTL-33, maybe.

This is.

<unk> four <unk> hundred <unk> maybe.

But is it really in the next few years is it 10 years, how long could be awhile and honestly very few people are going to spend all the money on gene editing to treat that few number so they're trying to do the bigger market at some point, maybe that will happen, but right now we feel comfortable as the program. We can sell now that works well.

works well, it's pretty convenient, doesn't have any unknown genetic...

Well, it's a pretty convenient doesn't have any unknown genetic issues that are yet to be figured out and so we're comfortable there is a good place for it in our portfolio at this point in time.

issues that are yet to be figured out and so we're comfortable there's a good place for it in our portfolio at this point in time.

But we're watching Gene Edding just like all of you, and they'll have ups and then downs.

But we're we're watching gene editing just like all of you and they will have ups and downs.

For you it's 143.

Overall dempsey by the FDA are generally not considered sufficiently clinical in their mind, there have been situations, where it didn't correlate well, though I think with anabolic agents that correlate better with outcomes.

So their requirement was to have clinically observed fractures to be the primary end point.

Their requirement was to have clinically observed fractures to be the primary endpoint what.

What we know from the data an asteroid that there were trends to fraction of proven the study with not very big and didn't have enough time.

But our view of it was that the bone mineral density improvements in the trend and fractures that we're seeing in the higher dose patients would be readily it would be clinically important and we feel comfortable that work second thing remember that Astro city with adults.

would be clinically important and we feel comfortable that will work. Second thing, remember that asteroid study was adult.

Adult bones don't respond like kid bones, and that's why I remember with XLH we got out of a dolphin to pee.

Bonds don't respond like Kid bones, and Thats why I remember in <unk>, we got out of adults with <unk> and peds are what drive the powerful efficacy story same things can be true for your excellent three kids bonds respond much greater much faster and we will remodel faster and build bone faster and so I'm very confident that in that.

P's are what drive the powerful advocacy story. Same thing is going to be true for UX 143. Kids bones respond much greater, much faster, and will remodel faster and build bone faster. And so I'm very confident that in that group, that we can improve fractures even more readily than you would in adults.

Through that.

That we can improve fractured even more readily than you would in adults.

So that's why we're pretty comfortable. That was true, by the way, in kids. Everything we did in kids worked faster and more powerful. In fact, people said it should take two years to see bone change, remember, in XLH. But in kids...

That's why we're we're pretty comfortable that was true by the way Im sure, but everything I think we didn't kids work faster and more powerful in.

In fact people said it should take two years to see bone changes merriman escalate, but in kids.

Actually you got 80% of the benefit in nine months only that was unexpected to some but as a pediatrician I like kids, because they get better and that's why I went into pediatric medicine originally.

As opposed to a correct.

Alright. Thanks.

Thanks very much.

Thank you and our next question comes from the line of Solveen Richter with Goldman Sachs. Your line is open. Please go ahead.

Good.

Thank you and our next question comes from the line of <unk> Richter with Goldman Sachs. Your line is open. Please go ahead.

Hey, thanks for taking your question. This is Elizabeth on for Salveen for your 2022 Chris Vida guidance. So wondering if you could comment on the breakdown you expect may come from North America versus the other rest of world geographies.

Well generally we don't make that breakdown for the sole purpose of allowing Eric the room to do what he has to do to get the sales there, but Eric I don't know if you wanted to comment I don't think we've made the breakdown in the past.

I'll comment just a bit and then just from the numbers and you can jump in. So we put in the press release that the North American territories were 171 million last year and other product sales, although we didn't break that down, but it's mostly Chris B that's coming from Latin America, was about 21 million. So that gives you the magnitude of difference within that guidance.

I'll comment just a bit and then just from the numbers Alright, gentlemen, alright, yes.

Probably in the press release that.

In North America territories for $171 million last year and other product sales, although we didn't break that down, but it's mostly <unk>.

This data.

Coming from Latin America, with about 21 million. So that gives you the point the magnitude of difference within that guidance.

So we continue to see very strong growth of Crespita in Latin America, but generally the biggest growth and the largest numbers clearly come from North America. Eric, I don't know if you want to add anything.

We continue to see very strong growth at Christina.

Latin America, but generally the biggest.

Growth in that large numbers clearly North America.

Eric you want to add anything more.

Sorry, just jumping. We're set. So Elizabeth, there's your answer.

Exactly what I was what I'm, saying.

Alright.

So there's that.

There's your answer.

Thank you Greg.

Thank you. And our next question comes from the line of Joseph Swartz with SVB Securities. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Joseph Schwartz with SBB Securities. Your line is open. Please go ahead.

Thanks very much. At the FAST conference, I guess I'll preface this by saying my first question is on Angelman and my second is not.

Alright, thanks very much.

The first conference I guess I'll preface this by saying My first question is on Angelman and my second is not.

At the FAST conference late last year, Dr. Dindo emphasized the value of preclinical models for Angelman. And so I was wondering if, particularly the PIG model, and I was wondering if you studied GTX 102 in the PIG model, and if so, what did you see with respect to the therapeutic index and dose response of GTX 102? And then is any of that of value and...

But.

At the SaaS conference late last year, Dr. Dinardo emphasize the value of.

Preclinical models for instrument and so I was wondering is particularly the pig model and I was wondering a few studies Gtx 102 in the big model and if so what did you see with respect to the therapeutic index and dose response of Gtx 102, and then is any of that.

working out to be in line with what you're observing in patients now.

<unk> and.

Working out to be in line with what you are observing patients now.

Yes, well, Dr. Dindo, of course, at Texas A&M would...

Yes, well, Dr. Dan, though of course that Texas A&M wood.

we talked about animal models being the ag school it is, but and the pig was more recently developed. So we don't actually have the GX1 data in the pig. They were developing the pig. They got it done now. But now we're in the clinic. So we haven't gone back to the pig with GX1. So I couldn't really answer those details.

We've talked about in animal models.

The AG school it is but.

And the pig was more recently developed so we haven't we don't actually have the J T. J fluent data the pig they were developing the pig. They got it done now and now we are in the clinic. So we haven't gone back to the pig with GT 1000, So I couldnt really answer those details.

I think the pig is interesting because it acts like angel and patience humans. It has, it doesn't have a stranger anxiety. It will come up to strange where most pigs are reluctant to come up to strangers. So there's these subtle behavioral patterns which are retained, which are interesting. But we haven't done the work yet, but I do think it could be helpful in other work in terms of developing additional improvements to the molecule or other types of approaches. Good.

I think the pig is interesting because it acts like angelman patients humans has it doesn't have a stranger things.

<unk> it will come up with a strange where most pigs are reluctant to come up with strangers. So theres. These subtle behavioral patterns, which are retained which are interesting.

But we haven't done the work yet, but I do think it could be helpful. In other work in terms of developing additional improvements to the molecule or other types of approaches but.

The truth is that fundamentally pig or whatever or monkey, you gotta deal with human patients to figure out what's happening and so.

The truth is that.

Fundamentally pig or whatever or monkey you've got.

To deal with given patient to figure out what's happening and so.

But I don't think we're going to find a path forward in the clinic.

Okay.

And then given your seamless Wilson disease study will have a couple of decision or data points.

Was wondering if you can give us a sense of.

When we might hear something first about the effect and the dose that will be taken into the pivotal portion of the study.

Sure, we will have an interim assessment of the program. But because the blinded program, we won't be able to disclose all the data we have. But our expectation, now the study didn't start, it's just starting now. So the timeline to get that interim is not going to be this year now because of where we are in 2020.

Sure we will have an interim assessment of the program, but because the blinded program, we won't be able to disclose all of the data that we have but our expectation, though steady didn't start is just starting now so the timeline to get that interim is not going to be this year.

Our expectation is to be able to know what the dosing response looks like, that the drug is working, that there is an impact on the markers of importance, and that...

Now because of where we are in time, but our expectation is to be able to know what the dosing response looks like that the drug is working that there is an impact on the markers of importance and that.

We are.

Choosing a dose and proceeding so that's the kind of level of granularity probably will provide and we will have to be careful about it because we just don't want to having that.

Damages the objectivity of the phase III study, but it should be enough to tell you the drug work here's the dose and we're seeing the phase III.

Okay, great. Thank you.

Thank you and our next question comes from the line of June Lee with Truist Securities. Your line is open. Go ahead.

Thank you and our next question comes from the line of Jim <unk> with <unk> Securities. Your line is open. Please go ahead.

Hey, Thanks for taking our question for.

<unk> for the Angelman data by midyear is your goal to have all Canada and Youll see patients on 14 milligram dose before your topline data.

Very interesting. We'll start with the last one. Mid-year is Q2 or Q3.

Very interesting.

I'll start with the last one mid year is Q2 or Q3.

As broad enough to really be annoying to all of you. So thats why we pick it that way.

But the truth is we have to get through a number of steps and get the study.

Executed.

The study is the protocol worthy they escalate after two doses and then they can escalate every three months during the maintenance phase further however, getting the 2014 will take a number of months. If we were to get there. So your question is can we just jumped doses.

Not in normal clinical protocol to jumped doses. So we are going to look at the data we have as we get to mid year and our expectation instead of jumping dose of June is to see where we're at and initiate an expansion cohort right, which would allow us to start dosing at a higher level now of dose level, let's say that's cleared by the data so far.

and initiate an expansion cohort, right, which would allow us to start dosing at a higher level now, a dose level, let's say, that's cleared by the data so far, but start at that dose level and now load with four doses at that higher level. So to get what you're getting at, June , by doing that, it'll allow us to jump efficacy a little further if we're not at our – where we want to be by the time we're at midyear, and that'll allow us to jump the dose.

Let's start at that dose level and now load with four doses at that higher level. So again, what youre getting at June by doing that allow us to jump efficacy a little further if we're not at our we want to be by the time, we're at mid year and that will allow us to jump the dose a.

A bit higher and continue ahead. We have to work through the safety window and establish a therapeutic window. I think.

A bit higher and continue ahead, we have to work through the safety window and establish a therapeutic window I think.

Well, we've seen so far there is a therapeutic window. We just need to figure out on what it will take to get the dose that gives us the kind of efficacy we think would be meaningful for patients.

What we've seen so far there is a therapeutic window, we just need to figure out.

We will take to get the dose that gives us the kind of efficacy, we think would be meaningful for patients. So.

Rather than jumping, both patients will continue, we'll add an expansion core art, which will jump up another level and then titrate from there and that will hopefully give us that dose, this dose, somewhere between all that information. We'd expect to have.

Rather than jumping will both piece will continue will add an expansion cohort, which will jump up another level and then titrate from there and that will hopefully give us that dose this dose somewhere between all of that information we would expect to have.

clarity later in the year by what we're going to run in phase three.

Clarity later in the year by what we're going to run in phase III.

And then, quickly, are there any more planned meetings for the Data Safety Monitoring Board? These are not pre-specified.

Got it and then.

Quickly.

Are there any more planned.

Meeting for the data safety monitoring board or <unk>.

Well, yeah, the two pre-specified were related to the further enrollment or expansion of the enrollment. That's all those have happened, but they will meet on a regular rhythm cadence because they need to continuously evaluate safety that's gone going. Of course, if a low extremity event happened, they would be notified immediately and have an ad hoc meeting, but there is a regular cadence that they are going to be doing, but there's no special triggers yet, except a safety event.

Is there no pre specified.

Yes.

Two pre specified were related to the further enrollment or expansion of the enrollment and thats all those would happen, but they will meet on a regular rhythm and cadence because they needed what we continuously evaluate safety that's gone going of course, if a lower extremity then happen they would be notified immediately and have an AD hoc meeting, but there is a regular cadence that.

That they are going to be doing but there is no special triggers yet except a safety event.

otherwise it's a regular cadence of meeting as the data goes forward.

Otherwise, it's a regular cadence of meeting a detailed go forward.

Thank you and our next question comes from the line of Jeff Hung with Morgan Stanley . Your line is open. Go ahead.

Alright, thank you.

Thank you and our next question comes from the line of Jeff Hung with Morgan Stanley . Your line is open. Please go ahead.

Thanks for taking the questions for Keith what considerations beyond the indication we're there for the partnerships such as you mentioned geographic expansion to APAC and further into Europe , and then how important is the potential for the expansion.

Okay.

So.

Because there are some patients down.

in South Africa and other places. So we are going to support, of course, any patients in any country. And there's a requirement that we certainly commercialize in a broad array of countries that we'll be working on.

In.

South Africa and other places so we are going to support of course any patients in any country.

And there is there is a requirement that we certainly commercialized.

In a broad array of countries.

Because Asia is there, we wanted to go into this, if Keith agrees with the tool to actually go and have Japanese patient data in the program.

That will be working on.

Because Asia is an area. We wanted to go into this with the tool to actually go and it has Japanese patient data in the program.

And the Japanese KOL involved was very, very positive on the study and very wants to help us get it approved in Japan quickly. So we have a package that's already potentially filed in Japan that should get us going in Japan earlier. So that will be part of our immediate expansion of the filing.

And the Japanese quell kols, while very very positive on the steady and very well to help us get it approved Japan quickly. So we have a packages already potentially file in Japan that should get us going in Japan earlier, so that will be part of our immediate expansion of the filing.

So, beyond that, I don't think that it's worth going into more detail. With regard to the...

So beyond that I don't think it's worth going into more detail with regard to the.

Making taking the options, it's really about us looking at where the development program is going and understanding the current data set they have.

At that point, which was set by time will will sit down and have a discussion with them about going forward.

<unk>.

a drug that's doing something very profound and important for these patients.

At this point I think it's.

A drug that's doing something very profound and important for these patients and.

I would say that that effect is so profound that most patients would I would think would want to get treated with it.

So we're highly encouraged we would expect to move forward at this point in time.

And then as a follow up to the question on Latin America, what are the key factors for further growth in Latin America this year?

And then as a follow up to the question on Latin America, what are the key factors for further growth in Latin America. This year.

Well, Latin America is always the story is always been. We have a great team. By the way, we have like some of the best people in Latin America and that team. They've done this well for a lot of rare disease program. The challenge has always been the politics and code that regard to reimbursement.

Well Latin America is always the story has always been we have a great team by the way we have like some of the best people in Latin America and that team has done.

Done this well for a lot of rare disease program. The challenge has always been the politics in Covid regard to reimbursement.

In Brazil, I think one of the important pieces that we've gotten through the reverse of a process now setting at the final step. So once that happens, then there'll be a set agreed price and there will be the ability to expand in Brazil further.

In Brazil, I think one of the important pieces that we've gotten through the reverse with process now setting the final steps.

That happens then there'll be a set of great price and there will be ability to expand in Brazil further.

In other countries, we're certainly working on filings and working on name-patient sales, and we'll begin adding where we can, working through reimbursement. But we are seeing traction now and growth in Latin America. I don't know if there's anything else, Eric, you might want to add to the Latin America growth story at this point.

In other countries, we're certainly working with working on filings and were going to named patient sales and we will begin adding where we can working through reimbursement, but we are seeing traction now and in growth in Latin America I don't know if theres anything else, Eric you might want to add to the Latin America growth story at this point.

No I think just as similar as we did in North America, and particularly in the U S with growth, we continue to expand to find more.

Patients.

As we reached out further into the community setting.

Something similar will occur in Brazil, especially as we obtain full reimbursement and we can.

Going to full commercialization.

Promotional activities.

Yes, I think thats going to be important so thanks, Eric.

Thank you. And our next question comes from the line of Lisa Baco with Evercore ISI. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Lisa <unk> with Evercore ISI. Your line is open. Please go ahead.

Hi, yeah, just one quick financial question and most of my questions have been answered, but maybe just one then quick one on Angelman. So, can you just give us some, you know, parameters to think about.

Hi, Yes, just one quick financial question and most of my questions have been answered, but maybe just one quick one on Angelman. So can you just.

Give us some.

For spend this year, I was just looking at your R and D number up a bit. Is that a good run? Right? To think about, or maybe we can just walk us through the shape for the year. Especially of R and D. Thanks.

Parameters to think about.

For our spend this year.

I was just looking at your R&D number.

Is that a good.

Run rate to think about or maybe you can just walk us through the shape for the year, especially if R&D. Thanks.

Sure, there's obviously there is some increase in spend as Marty's put out. Marty kind of described it a little more. There have been some 1 time items too in the mix. So Marty, why don't you. Yeah.

Sure.

Obviously, there is some increase in spend as Marty Marty you kind of describe it a little more there'd been some one time items too in the mix. So Marty why don't you give them.

Yeah, we highlighted the $50 million upfront collaboration that's in there. But, you know, right now with our development pipeline and late stage programs and our work in gene therapy, etc., we do think we'll have some growth in R&D going into 2022.

Yes.

Yes, we highlighted that $50 million upfront.

And that's in there right.

Right now with our development pipeline in late stage programs in our work in gene therapy et cetera.

We'll have some.

Some growth in R&D going into 2022.

mostly on the R&D line, I would say FMA, other than the focus on FTSE as we build up reimbursement in multiple countries in Europe will stay pretty much the same.

Mostly on the R&D line I would say.

<unk>.

And then the focus on SCS.

As we build out the reimbursement in countries in Europe .

we would expect continued growth in our next year for sure.

We will stay pretty much fixed.

We would expect continued growth in the next year for sure.

Okay, thanks. And then just on to Angel Minns, are there any like biomarkers or things like that, that you're looking at to help guide you and you know that would be sort of

Okay. Thanks, and then just on <unk>.

Onto.

And gentlemen are there any like biomarkers or things like that I think are looking at to help guide you and that would be sort of.

I think that's indicative of our kind of telling with respect to you know the other things that we're looking at.

Indicative of our.

Kind of tying with respect to the other metrics youre looking at.

Sure, well first of all the soluble biomarkers like UB3A, we presented it fast.

Sure well first of all the soluble biomarkers like <unk>, we presented it fast the fact.

What people thought where you'd be three and spinal fluid with probably blood contamination, because there is <unk> blood cells and so it turned out the trace amounts of <unk> found in the spinal fluid may very well do.

Leak, a little bit of blood in the tap.

which means that they're probably detecting EV3 in the spinal fluid, it's not going to be a kind of biomarker, but...

Which means that theyre, probably detecting <unk> three in the spinal fluid is not going to be a kind of a biomarker, but right redirect leases to look at the neurophysiology and thats the Delta power <unk> the <unk>.

What I'd read directly is to look at the neurophysiology, and that's the delta power EEG. The EEG is now not dependent on patient's thinking or whatever they're doing. Looking at neurologic function and what we showed, and there was an update that you guys should look at.

<unk> is now not dependent on patient thinking or whatever they're doing it looking at neurologic function and what we showed in there wasn't updated fast that you guys should look at more detailed data on the <unk> of the patients in the trial looking at Epileptiform and Delta powers showing changes in neuro busy.

more detailed data on the EEGs of the patients in the trial looking at epileptiform and Delta powers and showing changes in neurophysiology in those patients that were meaningful.

And those patients that were meaningful so I think it shows you that it is not just subjective view of the patient that better.

These narrow physiological evidence and I would look at that neurophysiology is being probably the best biomarker type information would tell you that something fundamental is happening in these very abnormal brains are starting to respond differently to stimuli than they did before.

Yeah.

Okay. Thank you.

Thank you and our next question comes from the line of Joel Beattie with Baird. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Joel Beatty with Baird. Your line is open. Please go ahead.

Hi, thanks for taking the question. The first one is on EPCISA outside of the US. After approval, how fast could the ramp up in sales be compared to what might otherwise be typical for rare disease drugs? And then the second question is for Wilson's disease in the stage one part of the trial, how much potential is there at that time to learn about NESCST and neural endpoints?

Alright, thanks for taking the questions first one is on the outside of the U S. FDA approval, how fast the ramp up in sales be compared to what might otherwise be typical for a rare disease drugs and then second question is for Wilson's disease.

The phase one part of the trial.

How much potential is there that time to learn about any efficacy neuro endpoints.

Okay, so the first question on outside the US was about EPCISA or something else.

Okay. So the first question on outside the U S was about <unk> <unk> or something else.

Yes.

Yes, so it's a little hard for us to guide for sales outside yet I mean, I think it's this year's me while reimbursement in.

In Europe , getting it set and going in the other countries are going to be somewhat behind them. So I wouldn't be able to tell you much about how the growth is going to be but I would expect that that of Europe .

But I would expect that you're a.

you know, an XUS launch is going to take a couple years of filings and approvals and reimbursement work to get...............

And ex U S launch is going to take a couple of years of filings and approvals and reimbursement work to get dramatically going but this year is all about Europe and thats, what the team will be focusing on.

dramatically going, but this year is all about Europe , and that's what the team will be focusing on.

With regard to Wilson.

Turning to determine their difference would be hard to do on dosing. So we're going to focus the dosing on.

The biomarkers of copper control and theirs.

Really good data to say that copper control in its various forms.

Should give us the right answer in dosing.

all things equal, if the highest dose gives us the highest ruloplasm levels, which it likely would, and assuming that it's safe, the same safety as the E13 dose, and I would think the highest dose is going to end up most likely to be the dose.

And basically I would say to you that if.

All things equal if the highest dose gives us the highest gorilla plasma levels, which it likely would and assuming that it's safe for the same safety of the <unk> dose and I would think the highest dose is going to end up most likely to be the dose.

And.

So there shouldnt be that much mystery, because we're pretty clear that in this range that the dose that.

In the low <unk> range that 2013 should be better than 2013, and we would expect.

Assuming safety excellent that that would end up being coming the dose.

But.

Because it's a new treatment first in man, we have to we have to work through the process right and Thats why there are three doses.

<unk> once you get enough copper detoxification occurring that going higher doesn't necessarily get you more detoxifying, which we'll see but the thrill of plasma and part of the story is about copper distribution and we know from the animals, that's a little harder to achieve and therefore I am personally and want to focus on the fact, we are actually <unk>.

Drawing some level of copper distribution, which to me would be the real reason why you do gene therapy that youre, not just getting rid of toxic copper actually restoring copper homeostasis and that would be the real benefit of gene therapy over everything else.

Great. Thank you.

Thank you and our next question comes online of Laura Shickle with Woodbush. Your line is open. Please go ahead.

Thank you and our next question comes from the line of Laura Chico with Wedbush. Your line is open. Please go ahead.

Good afternoon. Thanks for fitting me in. I just have one on Angelman. You know, assuming the best case scenario and you're advancing towards pivotal studies. And I'm wondering if you could talk about kind of on the execution side. What would be a feasible number of recruitment sites in the US Thanks. That's that's a very.

Good afternoon, and thanks for fitting me in I just have one on angelman.

Assuming the best case scenario and youre advancing towards pivotal studies.

If you could talk about kind of on the execution side, what would be a feasible number of recruitment sites in the U S. Thanks.

That's a very interesting clinical ops question.

Laura.

That's a question we've talked about a lot frankly.

As usual tendency to run with huge numbers of sites, but I would say most grade studies run with the smaller number of really good sites and that would be our focus.

There are a lot of angelman patients that a lot of centers that have a lot of patients.

if the drug data from our phase two study are as promising as we hope they will be.

If the drug data from our phase II study are as promising as we hope they will be.

then I think the ability to enroll a study will be there. And we just need sites who can manage.

Then I think the ability to enroll a study will be there and we just need size who can manage.

is somewhere in there and therefore we're going to, it's going to be an international study, not just US and.

Probably less than 200.

We're in there and therefore, we're going to it's going to be an international study not just U S.

Our hope would be that it would be only a 6 month study where we look at loading and show the difference of a clinical effect over a loading period. So I can't tell you the exact number on a number of sites. I don't think I'd venture that guess at this moment in time.

<unk>.

Our hope would be that it would be only a six month study, where we look at loading and show the difference of clinical effect over a loading period.

So I can't tell you exact number on the number of sites I don't think I'd venture that guess at this moment in time, but.

If there is any issue or question Youre asking about like are there going to be competition for patients and sites. While there are other programs and Adrian I think there could be competition for patients, but I also point out there was a.

A lot as when patients right. So we think there'll be enough patients to get our studies enrolled even in the context of other programs ongoing.

But more important with now is showing what our drug can do in that safe in phase II and then everything else will come.

If that is successful.

Very helpful. Thanks.

Thank you. And this does conclude today's question and answer session. And I would like to turn the conference back over to Joshua Higa for any further remarks.

Thank you and this does conclude today's question and answer session and I would like to turn the conference back over to Joshua Hager for any further remarks.

Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at IR at Ultragenics.com. Thanks for joining us.

Thank you. This concludes today's call. They are any additional questions. Please contact us by phone or at IR at Ultra <unk> Dot com, thanks for joining us today.

This concludes today's conference call. Thank you for participating. You may now disconnect.

This concludes today's conference call. Thank you for participating you may now disconnect.

Q4 2021 Ultragenyx Pharmaceutical Inc Earnings Call

Request a DemoDemo

RARE

Ultragenyx Pharmaceutical

Earnings