Q1 2022 Ultragenyx Pharmaceutical Inc Earnings Call

May 5, 2022

[music].

Good day and thank you for standing by.

Good day, and thank you for standing by welcome to the Altra Genetics first quarter 2022 financial results and corporate update conference call. At this time all participants are in a listen only mode. After the speaker presentation. There will be a question and answer session to ask a question. During the session you will need to press star one on your telephone. Please be advised that today's conference is being recorded if you would.

Welcome to the Ultragenyx first quarter 2022 financial results and corporate update conference call.

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

After the speaker presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one on your telephone.

Please be advised that today's conference is being recorded.

If you'd like to have assistance during the conference, please press star zero.

I would now like to hand the conference over to your speaker today, Joshua Higa.

To have assistance during the conference. Please press Star Zero I would now like to hand, the conference over to your speaker today Joshua Hager.

Good afternoon, and welcome to the Ultragenyx Pharmaceutical financial results and corporate update conference call for the first quarter 2022.

Thank you for participating.

Good afternoon, and welcome to the Ultra <unk> Pharmaceuticals financial results and corporate update conference call for the first quarter 2022, 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> director of Investor Relations. Joining me on this call are <unk> chief executive.

We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com.

You may now disconnect.

Good day and thank you for standing by.

I am Joshua Higa, Director of Investor Relations.

Welcome to the Ultragenyx First Quarter 2022 Financial Results and Corporate Update conference call.

Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Erik Harris, Chief Commercial Officer, Marty Deer, Chief Financial Officer, and Camille Bedrosian, Chief Medical Officer.

<unk> Officer, and President, Eric Harris, Chief Commercial Officer, Mardi Dier, Chief Financial Officer, and Camille Bedrosian, Chief Medical Officer, I would like to remind everyone that during today's call. We will be making forward looking statements. These statements are subject to certain risks and uncertainties and our actual results may differ materially please refer.

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

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

And to the risk factors discussed in our latest SEC filings I will now turn the call over to him.

I'll now turn the call over to, Thanks, Josh, and good afternoon, everyone.

At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question and answer session.

To ask a question during the session, you will need to press star 1 on your telephone.

Thanks, Josh and good afternoon, everyone.

In the first quarter, we continue to make progress across our diverse clinical and commercial programs.

In the first quarter, we continued to make progress across our diverse clinical and commercial programs.

In the late-stage clinical pipeline, we're now enrolling patients in three registrational studies, with a fourth to initiate later this year. This includes the three gene therapy programs for Glycogen Storer Disease Type 1a, Wilson Disease, and Ornithine Transcarbamylase Deficiency, as well as our anti-sclerostin antibody for Osteogenesis Imperfecta.

In the late stage clinical pipeline, we're now enrolling patients in three Registrational studies with the fourth to initiate later this year.

This includes the three gene therapy programs for glycogen storage disease type one a.

Wilson disease in ornithine, <unk> deficiency, as well as our anti <unk> antibody for osteogenesis imperfecta.

The GTX-102 study for Angelman's Syndrome is progressing well, and we remain confident in the program.

The Gtx 102 study for Angelman syndrome is progressing well and we remain confident in the program.

The results we shared in 2020 from the original five patients led us to reimagine what is possible for patients with Angeman syndrome. Given the importance of this program, we've looked at various ways to accelerate this program.

The results we shared in 2020 from the original five patients led us to re imagine what is possible for patients with Angelman syndrome.

Given the importance of this program we've looked at ways various ways to accelerate this program and.

And recently, we amended our agreement with Genetics to allow us an additional option to acquire them at an earlier time point based on interim data.

And recently, we amended our agreement with genetics to allow us an additional option to acquire them at an earlier time point based on interim data.

I'll let Camille share more in her section about the favorable safety profile and enrollment status across the regions.

I'll, let camille share more in her section about the favorable safety profile and enrollment status across the regions.

We also look forward to providing a more robust interim update in mid-2022.

We also look forward to providing more robust interim update in mid 2022.

On the commercial side.

On the commercial side the teams continued developing and executing their plans to define more patients who could benefit from Chris Vita those will the unmet savi.

Teams continue developing and executing their plans to define more patients who could benefit from CRISVita, Dojolvi, and Mepsevi. These efforts are supported by the work our clinical and regulatory teams are doing with country-specific authorities to enable greater access to these therapies.

These efforts are supported by the work our clinical and regulatory teams are doing with country specific authorities to enable greater access to these therapies.

In the first quarter, we also closed on the strategic partnership with Regeneron, which pairs our expertise in global rare disease launches with the industry leader in antibody drug discovery and development.

In the first quarter. We also closed on the strategic partnership with Regeneron, which pairs our expertise in global rare disease launches with the industry leader in antibody drug discovery and development.

We'll leverage our global commercial medical fares regulatory functions to bring us KISA, A novel, high potent, and approved antibody to patients where the current standard of care does not adequately reduce the LDL cholesterol in patients with HFH.

We will leverage our global commercial medical affairs regulatory function to bring its Keith.

<unk> high potent an approved antibody to patients where the current standard of care does not adequately reduce the LDL cholesterol in patients with HMH.

Since closing the deal, we transferred the marketing authorization in Europe and have begun the process to submit reimbursement dossiers. While this review process and negotiations can take time, we will leverage the team that currently supports MepSav and Dojovi to respond to requests for named patient access within Europe.

Since closing the deal we transferred the marketing authorization in Europe and have begun the process to submit reimbursement dossiers.

While this review process of negotiations can take time, we will leverage the team that currently supports <unk> to respond to requests for named patient access within Europe .

Feedback from the KOL community has been enthusiastic for the important role that Keith could play in the management of familial hypercholesterolemia.

Feedback from the Kols community has been enthusiastic for the important role of Keith could play in the management of familial hypercholesterolemia.

If KESA gives us a fourth product across five different indications that will be generating revenue for the company, this creates a diversified base of value that will help support our continued clinical execution for years to come.

Keith It gives us a fourth product across five different indications that will generate be generating revenue for the company.

Creates a diversified base of value that will help support our continued clinical execution for years to come.

I'll let the team go into more detail on their progress in the quarter.

I'll, let the team go into more detail on their progress in the quarter, Eric can you begin.

Eric, can you begin?

Thank you, Emil, and good afternoon, everyone.

Please be advised that today's conference is being recorded.

Thank you Amy and good afternoon, everyone.

If you'd like to have assistance during the conference, please press star 0.

Commercialization teams have continued to adapt and evolve this strategy, to meet the constantly changing landscape.

Commercialization teams have continued to adapt and evolve their strategies to meet the constantly changing landscape for Christina.

For CRISPR-Vita, within the North American territory, the strong underlying demand from adult and pediatric patients.

I would now like to hand the conference over to your speaker today, Joshua Higa.

Within the North American territory with strong underlying demand from adult and pediatric patients with <unk> and Tio continues.

XLH and TIO continue. Compliance among patients who are already on therapy remains high, with patients reflecting on how much better they feel once they start receiving Crisvita. In the first quarter, approximately 80 new patients began therapy, which is consistent with the steady growth we have seen over the last few quarters.

Clients among patients who are already on therapy remains high with patients reflecting on how much better they feel once they start receiving christina.

In the first quarter approximately 80, new patients began therapy, which is consistent with the steady growth we have seen over the last few quarters.

These increases are largely driven by the community prescribers.

These increases are largely driven by the community prescribers were nearly 50, new doctors wrote a prescription in the first quarter.

We're nearly 50 new doctors, wrote a prescription in the first quarter.

Good afternoon, and welcome to the Ultragenyx Pharmaceutical financial results and corporate update conference call for the first quarter 2022.

Latin America.

Latin America, we are continuing to see accelerating demand for Chris meter drift.

We are continuing to see accelerating demand for Crisprida. Driven by Patient-Speaking Therapy through the NAMED Patient Program. This is particularly the case in Brazil, the largest market in the region.

Driven by patient seeking therapy through the named patient programs.

This is particularly the case in Brazil, the largest market in the region.

Where we are in the final stages of full reimbursement negotiations with the authorities.

Ordering in this region can be variable from quarter to quarter, but it is clear there is a strong demand for CRISPR from the patient and medical community. Perceived revenue in the first quarter, 2022, grew 29% compared to the first quarter of 2021.

Ordering in this region can be variable from quarter to quarter, but it is clear there is a strong demand for prestige when the patient and medical communities.

We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com.

For <unk> revenue in the first quarter 2022 grew 29% compared to the first quarter of 2021.

As is typical, there was some seasonality as patients worked through the reauthorization process with their insurance providers at the beginning of the year.

I am Joshua Higa, Director of Investor Relations.

As is typical with some seasonality as patients work through the reauthorization process with their insurance providers beginning of the year.

As we saw in 2021.

We expect stronger revenues in the second half of the year, and we maintain that 2022 the feeder revenue in Ultragenyx territories will be between $250 and $260 million, representing 30% growth in the product's fifth year.

We expect stronger revenues in the second half of the year and we maintain that 2022.

Peter revenue and ultra Genex territories will be between $250 million to $260 million, representing 40% growth products fifth year.

Turning now to the Jill.

Turning now to the GOP as.

As a reminder, we will no longer provide detailed start, and other metrics for this program. Since we are past the early quarters of launch. In the U.S., the number of new start forms in patients on reimbursed therapy are consistent with the steady growth we saw in recent quarters.

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

As a reminder, we will no longer provide detailed start form and other metrics for this program. Since we are past the early quarters of launch.

In the U S. The number of new start forms and patients on reimbursed therapy.

Consistent with the steady growth we saw in recent quarters.

While we are seeing utilization at nearly all of the major centers for inborn errors of metabolism.

While we are seeing utilization at nearly all of the major centers for inborn errors of metabolism, we have begun to find new prescribers at some of the neuromuscular centers of excellence we.

We have begun to find new prescribers at some of the neuromuscular centers of excellence.

We will increase our efforts on these specialists as we look to expand the network of prescribers.

All charities are funded by the U.S. Government.

Outside of the U S use of the Dolby continues through our main patient and early access programs in Europe .

Use of the Joby continues through our main patient and early access programs in Europe.

In France and Italy, there continues to be meaningful demand for our named patient program.

France, and Italy, there continues to be meaningful demand.

Our named patient program.

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

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

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

For the year, we are reaffirming the guidance range of $55 to $65 million that we put out in January.

For the year, we are reaffirming the guidance range of $55 million to $65 million.

That we put out in January .

I commend the team's work to generate more than 50% growth in this product's third year post-approval.

I commend the teams work to generate more than 50% growth in this product's third year post approval.

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

I'll now turn the call over to, Thanks, Josh, and good afternoon, everyone.

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

Thanks, Erik.

In the first quarter, we continue to make progress across our diverse clinical and commercial programs. In the late stage clinical pipeline, we're now enrolling patients in three registrational studies with a fourth to initiate later this year. This includes the three gene therapy programs for Glycogen Storer Disease Type 1a, Wilson Disease, and Ornithine Transcarbamylase Deficiency, as well as our anti-sclerostin antibody for Osteogenesis Imperfecta.

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

Earlier today, we issued a press release that included financial results for the quarter, which I will briefly summarize. Company revenue for the three months ended March 31, 2022 totaled $79.9 million. Chris Vita revenue in Ultragenyx territories were $54.6 million, including $45.2 million from the North America Profit Share territories and net product sales of $9.4 million in other regions.

Company revenue for the three months ended March 31, 2022 totaled $79 99.

Christy that revenue and ultra Genex territories were $54 6 million, including $45 2 million from the North American profit territory territories, and net product sales of nine 4 million in other regions.

Total royalty revenue for the sales of CRISPIDA in the European territory were $4.8 million.

Total royalty revenue for the sales of Christy that in the European territory were $4 8 million.

The Jolvi revenue for the first quarter of 2022 was $12.4 million.

<unk> revenue for the first quarter of 2022 was $12 4 million net savvy revenue for the same period was $4 9 million. We expect these revenue revenues may modestly increase over time.

MepSeve revenue for the same period was $4.9 million. We expect these revenues may modestly increase over time. We also recognize $3.2 million of revenue in the first quarter related to tech transfer as part of our strategic manufacturing partnership with Daiichi Senkyo around our PCL and HEC 293 technology. Recall in the fourth quarter of 2021, the technology transfer activities were substantially completed and revenue from this agreement going forward will be minimal.

We also recognized $3 2 million of revenue in the first quarter related to tech transfer as part of our strategic manufacturing partnership with Daiichi Sankyo around our PCL and heck to nine Trane technologies.

Recall in the fourth quarter of 2021, the technology transfer activities were substantially completed and revenue from this agreement going forward will be minimum.

Excluding Daiichi revenue in both periods, toe revenue has grown 35% in the quarter compared to the first quarter of 2021.

Excluding daiichi revenue in both periods total revenue has grown 35% in the quarter compared to the first quarter of 2021.

Our total operating expenses for the first quarter of 2022 were $216.6 million, which includes research and development expenses of $143.2 million, SG&A expenses of $67.3 million, and cost of sales of $6.1 million. I should note, this also includes expense related to non-cash, stock-based compensation of $29.4 million.

Our total operating expenses for the first quarter of 2022 were $216 6 million, which included research and development expenses of $143 2 million SG&A expenses at $67 3 million and cost of sales of $6 1 million.

Note. This also includes expense related to noncash stock based compensation of $29 4 million.

As we have discussed in prior quarters, we continue to expect our R&D spend to somewhat increase in 2022 as we support three pivotal gene therapy clinical studies, the UX143 Phase 2-3 clinical study in OI and Angelman Phase 1-2 study and the Phase 1-2 study for our most advanced mRNA program UX053 and GSD3 and a number of other preclinical activities as we get ready to advance the next programs into the clinic.

As we have discussed in prior quarters, we continue to expect expect our R&D spend to somewhat increase in 2022 as we support three pivotal gene therapy clinical studies.

The UX one for three phase three clinical study in <unk>, and Angelman and Angelman phase one two study and the phase III study for our most advanced mrna program <unk>, III and GSD III 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 FQISA.

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 quarter ended March 31 2022 net loss was 152.3 million or 219 per share. The net loss includes 9.3 million decrease in the fair value of equity investment. Our net cash used for the first quarter 2022 also includes the $30 million upfront payment for the closing of the Regeneron Collaboration Agreement and significant investments in our gene therapy manufacturing plant, which we are planning to be operational in 2023. We ended the quarter with approximately $814 million in cash, cash equivalents, and marketable securities.

For the quarter ended March 31, 2022, net loss was $152 3 million or $2 19 per share. The net loss includes $9 $3 million decrease in the fair value of equity investments.

Our net cash used for the first quarter 2022 also includes the $30 million upfront payment for the closing of the Regeneron collaboration agreement and significant investments in our gene therapy manufacturing plant, which we are planning to be operational in 2023.

We ended the quarter with approximately $814 million in cash cash equivalents and marketable securities. This puts us in a very solid position to achieve critical clinical milestones and expand our global commercial presence.

This puts us in a very solid position to achieve critical clinical milestones and expand our global commercial presence.

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.

The GTX-102 study for Angelman's Syndrome is progressing well and we remain confident in the program.

Thank you Marty and I too wish everyone. A good afternoon, and my section I will briefly provide status updates for our six clinical stage programs.

And I too wish everyone a good afternoon.

Putting the Gtx 102 phase one two study being conducted by our partner genetics.

Before turning the call back to Emil.

In my section, I will briefly provide status updates for our six clinical stage programs, including the GTX-102 Phase I-II study being conducted by our partner, Genetics, before turning the call back to Emil, starting with the gene therapy program.

Starting with the gene therapy programs.

DTX-401 for the treatment of glycogen storage disease type 1A or GSD-1A is currently dosing patients in the randomized placebo-controlled phase 3 study.

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

Similarly, UX701 for the treatment of Wilson Disease is currently dosing patients in a seamless Phase 1-2-3 randomized placebo-controlled study.

Similarly, <unk> 701 for the treatment of Wilson disease is currently dosing patients in our seamless phase 123 randomized placebo controlled study.

DTX-301 for the treatment of ornithine transcarbamylase or OTC deficiency is currently in the final stage of the study startup and site activation. We anticipate the first patients will enter the 4-8 week baseline screening period in mid-2022, after which they will be dosed in the phase 3 randomized placebo-controlled study.

<unk> for the treatment of ornithine <unk> or OTC deficiency is currently in the final stages of study startup and site activation.

We anticipate the first patients will enter the 4% to eight week baseline screening period in mid 2022, after which they will be dosed in the phase III randomized placebo controlled study.

Okay outside of gene therapy, you excellent four three or <unk>, an anti <unk> antibody has begun dosing patients in the seamless phase III study for pediatric and young adult patients with Osteo Genesis imperfecta.

Outside of gene therapy, UX143 or citruzumab, an anti-scarostin antibody, has begun dosing patients in the seamless Phase 2-3 study for pediatric and young adult patients with osteogenesis imperfecta.

We are also planning to initiate an additional study in children less than five years old in the second half of the year.

GTX-102, the ASO in development with our collaborator, Genetics, for patients with Angelman syndrome, continues to dose patients under the amended Phase 1-2 protocol. In the UK and Canada, both Cohorts 4 and 5 have expanded following a review of available safety data by their respective DSMBs. We began dosing patients in December, with some receiving up to five doses so far.

Gtx 102, the Asl in development with our collaborator genetics for patients with Angelman syndrome continues to dose patients under the amended phase one two protocol.

And recently, we amended our agreement with genetics to allow us an additional option to acquire them at an earlier time point based on interim data.

In the UK and Canada, both cohorts four and five have expanded following a review of available safety data by their respective DSM b.

I'll let Camille share more in her section about the favorable safety profile and enrollment status across the regions.

We began dosing patients in December with some receiving up to five doses so far.

As we have previously indicated, the initial assessments of these patients have shown early and encouraging signs of clinical activity in multiple domains, similar to that which we saw in the original five patients at these low doses. To date, there have been no drug-related safety issues or lower extremity weakness in the newly treated.

As we have previously indicated the initial assessments of these patients have shown early and encouraging signs of clinical activity in multiple domains similar to that which we saw in the original five patients at these low doses.

To date, there have been no drug related safety issues or lower extremity weakness in the newly treated patients.

In the U.S., eight patients allocated one-to-one in the drug and comparator groups have been enrolled. We have received some anecdotal reports of limited improvements from these patients being dosed who have received drug at the two-may dose level.

To reiterate, a most important finding for this stage of the study across all regions, There have been no reports of lower extremity weakness in any of the patients treated under the amended protocol.

We look forward to providing a more robust update on this program in mid-2022.

We also look forward to providing more robust interim updates in mid-2022.

UXO53, our first mRNA treatment modality being developed for glycogen storage disease type 3, is currently dosing patients in the single ascending dose arm of the phase 1-2 study. Preliminary data from that arm, as well as initiation of repeat dosing phase of the study, are anticipated in the second half of this year.

On the commercial side, teams continue developing and executing their plans to define more patients who could benefit from CRISVita, Dojolvi, and Mepsevi. These efforts are supported by the work our clinical and regulatory teams are doing with country-specific authorities to enable greater access to these therapies.

With these updates, I will now turn back the call to Emil.

Thank you.

We will leverage our global commercial medical affairs regulatory functions to bring us KISA, A novel, high potent, and approved antibody to patients where the current standard of care does not adequately reduce the LDL cholesterol in patients with HFH.

Since closing the deal, we transferred the marketing authorization in Europe and have begun the process to submit reimbursement dossiers. While this review process and negotiations can take time, we will leverage the team that currently supports MEP-7 Dojovi to respond to requests for named patient access within Europe.

Feedback from the KOL community has been enthusiastic for the important role that Keith could play in the management of familial hypercholesterolemia.

The PISA gives us a fourth product across five different indications that will be generating revenue for the company. This creates a diversified base of value that will help support our continued clinical execution for years to come.

I'll let the team go into more detail on their progress in the quarter.

Thank you, Camille.

Eric, can you begin?

For Gtx 102 in Angelman syndrome, who will provide an interim 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 continue to be confidence program look for opportunities to accelerate development.

Before we shift to the Q&A portion of the call, I'll provide a quick reminder of the key upcoming milestones for the company.

Thank you, Emil, and good afternoon, everyone.

Commercialization teams have continued to adapt and evolve this strategy, to meet the constantly changing landscape.

For CRISPRIDA, within the North American territory, the strong underlying demand from adult and pediatric patients.

XLH and TIO continue. Compliance among patients who are already on therapy remains high, with patients reflecting on how much better they feel once they start receiving CRISVITA. In the first quarter, approximately 80 new patients began therapy, which is consistent with the steady growth we have seen over the last few quarters.

These increases are largely driven by the community prescribers.

For GTX-102 and ANG1 syndrome, we'll provide an interim update in mid-2022 on cohorts 4 and 5 in the Canada and UK arms of the study, as well as available safety and efficacy data from the patients treated in the U.S. Continue to be confident in this program and look for opportunities to accelerate development.

Ordering in this region can be variable from quarter to quarter, but it is clear there's a strong demand for Presvita from the patient and medical community. Perceived revenue in the first quarter, 2022, grew 29% compared to the first quarter of 2021.

We're nearly 50 new doctors, wrote a prescription in the first quarter.

For U S 140, <unk> imperfecta will.

Latin America.

We are continuing to see accelerating demand for Chris Vito. Driven by Patients Seeking Therapy through the Named Patient Program. This is particularly a case in Brazil, the largest market in the region.

Where we are in the final stages of full reimbursement negotiations with the authorities.

For UX143 and oxygenus imperfecta, we'll continue enrolling patients in the phase two portion of the study and expect to provide an update on the dose strategy we have selected for the phase three portion in the second half of the year.

As is typical, there was some seasonality as patients worked through the reauthorization process with their insurance providers at the beginning of the year.

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

As we saw in 2021.

We expect stronger revenues in the second half of the year, and we maintain that 2022, the feeder revenue in Ultragenyx territories will be between $250 and $260 million, representing 30% growth in the product's fifth year.

Turning now to the Jill.

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

As a reminder, we will no longer provide detailed start, and other metrics for this program, as we are past the early quarters of launch. In the U.S., the number of new start forms and patients on reimbursed therapy are consistent with the steady growth we saw in recent quarters.

While we are seeing utilization at nearly all of the major centers for inborn errors of metabolism.

We have begun to find new prescribers at some of the neuromuscular centers of excellence.

We will increase our efforts on these specialists as we look to expand the network of prescribers.

Yeah.

Across the gene therapy pipeline, we'll continue enrolling the Phase 3 for DTX-401 and the Phase 1, 2, 3 for UX-701.

Outstanding.

Across the gene therapy pipeline, we'll continue enrolling the phase III for <unk> hundred one in the phase three for <unk> 701.

Use of the Joby continues through our main patient and early access programs in Europe.

We also expect to finalize study...

In France and Italy, there continues to be meaningful demand for our named patient program.

We also expect to finalize study.

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

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

Study Startup Activities for DTX-301 and Begin Dosing Patients in Mid-2022.

For the year, we are reaffirming the guidance range of $55 to $65 million that we put out in January.

Steady startup activities for <unk> 301, and begin dosing patients in mid 2022.

I commend the team's work to generate more than 50% growth in this product's third year post-approval.

On the manufacturing side, we will continue to build out our facility at Bedford, Massachusetts, which is on track to begin producing material next year.

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

On the manufacturing side, we will continue to build out our facility at Bedford, Massachusetts was on track to begin producing material next year.

For UXO53 in the second half of the year, we expect to share single-dose data from the first part of the Phase 1-2 study and to initiate the repeat dosing stage.

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

All these programs create a distinct opportunity to make a meaningful difference for patients with a rare genetic disease.

All of these programs create a distinct opportunity to make a meaningful difference for patients with a rare genetic disease.

We look forward to sharing further updates with you throughout the year.

Look forward to sharing further updates with you throughout the year. You also may have seen that we have launched our inaugural ESG report for 2021 last month, the support of the meaningful evolution to the journey we've been on for the last 12 years of the company.

You also may have seen that we have launched our inaugural ESG report for 2021 last month.

This report is a meaningful evolution of the journey we've been on for the last 12 years as a company.

We'll continue to build on this foundation and report on our progress.

We will continue to build on this foundation and report on our progress.

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

Thanks, Erik.

With that let's move onto your questions.

Operator, please provide the Q&A instructions.

Total royalty revenue for the sales of CRISPIDA in the European territory were $4.8 million.

Operator, please provide the Q&A instructions.

The Jolvi revenue for the first quarter of 2022 was $12.4 million.

MepSeve revenue for the same period was $4.9 million. We expect these revenues may modestly increase over time. We also recognize $3.2 million of revenue in the first quarter related to tech transfer as part of our strategic manufacturing partnership with Daiichi Senkyo around our PCL and HEC 293 technology. Recall in the fourth quarter of 2021, the technology transfer activities were substantially completed, and revenue from this agreement going forward will be minimal.

Excluding Daiichi revenue in both periods, toe revenue has grown 35% in the quarter compared to the first quarter of 2021.

Thank you.

Thank you as a reminder to ask a question you will need to press star one on your telephone withdraw your question press the pound key we ask that you limit your questions to one question and one follow up please standby, while we compile the Q&A roster.

As a reminder, to ask a question, you will need to press star 1 on your telephone.

To withdraw your question, press the pound key.

We ask that you limit your questions to one question and one follow-up.

Please stand by while we compile the Q&A roster.

Our first question comes from Gena Wang with Barclays.

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 FQISA.

Thank you for taking my questions I have two questions.

This puts us in a very solid position to achieve critical clinical milestones and expand our global commercial presence.

Joanne.

Thank you for taking my questions.

So maybe can you comment on any chemistry differences.

Locking equally asset.

Roche is locking UK asset and then my second question is based on the comments you made that early upbeat for the Gtx 102.

Should we expect some fast clinical benefit at the midyear update beyond the two CGI score improvement in two domains to support the right dose.

Thank you gena so on the chemistry differences I am I am.

Deeply familiar with the specifics of the Roche molecule and all the different linkages because there are a lot of linkages. We know that it has locked in clegg acid GAAP model like ours is there are some specific differences on the sequence no doubt and some other minor chemistry changes, but I think the biggest changes where differences between where these are targeted.

And the overall safety profile of a product it's not just the chemistry. It's also the dose and the potency that will determine it and we believe based where ours is targeted at is very potent and that the dose range will be at a lower end of the range.

Which is partly part related to the potency of the logic like asset type of ASO. So we're confident about the chemistry have while theyre both to have LMA blocked nucleic acid components I can't say it those differences are that you can make any conclusions from those differences alone.

I have two questions on Andrew Man's program.

Now with regard to the opt in the opt in just gives us an opportunity to execute earlier on interim data.

And it just gives an opportunity to potentially accelerate the program.

The decision on efficacy is not doesn't indicate.

That we would need more or better or worse efficacy is just option for us based on the interim data to execute the acquisition earlier.

Under a different somewhat different set of terms, but we think it is.

As a potential way for us to accelerate the program depending on what we see in announced mid year.

Thank you.

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

Thank you. Our next question comes from Eagle Djokovic with Citigroup.

Alright.

Sure.

Yes.

We do.

Operator.

Might not be related to our call.

We'll move on to your question.

Thank you, Marty.

And I too wish everyone a good afternoon.

<unk> Ahmad with Bank of America.

So, Emil, maybe can you comment on any chemistry differences between your log nuclear acid versus Roche's log nuclear acid?

Alright, okay. Thanks for taking my questions.

And my second question is, you know, based on comments you made that earlier opting for the GTX 102, should we expect some robust clinical benefit at the mid-year update beyond the two CGI score improvement in two domains to support the right dose?

GTX-401 for the treatment of Glycogen Storage Disease Type 1a or GSD-1a is currently dosing patients in the randomized placebo-controlled phase 3 study.

Similarly, UX701 for the treatment of Wilson Disease is currently dosing patients in a seamless Phase 1-2-3 randomized placebo-controlled study.

And I just wanted to get a sense from you on how you plan on aligning.

Protocol going forward between FDA, and EU regulators, assuming that youre going to move into your pivotal study for Angelman.

Thank you, Gena.

And then secondly can you talk about the cadence of growth for Christie, thus far it's starting to move into sort of the mid stage of growth.

What was the main growth driver in this quarter and where do you see the remaining.

For growth on a go forward basis. Thank you.

So, on the chemistry differences, I'm not deeply familiar with the specifics of the Roche molecule and all the different linkages, because there are a lot of linkages.

Good.

We know that it has lochnucleic acid, GAT-mer, like ours is.

There are some specific differences on the sequence, no doubt, and some other minor chemistry changes, but I think the biggest change is differences between where these are targeted.

I will do with the protocol piece first and Eric maybe you can talk about the areas of growth for Christina after I finish with the first part.

In the overall safety profile of a product, it's not just the chemistry.

It's also the dose and the potency that will determine it, and we believe, based where ours is targeted, it is very potent and that the dose range will be at a lower end of the range, which is partly related to the potency of the lochnucleic acid type of ASO.

So, we're confident about the chemistry we have, and while they both have LNA lochnucleic acid components, I can't say that you can make any conclusions from those differences alone.

So on aligning protocols, it's not actually that difficult both protocols are treating.

Essentially a once a month, but it's just a different dose and regimen for administration. So our expectation to align them will align them in the phase II, we will take our data from ex U S from Canada, and the UK that show us that the drug is safe and that the new administration strategy.

As appropriate.

And bring that data along with other safety data, we have to the U S and request that they opened essentially that an amendment that will align all three regions under the same protocol.

We think we have enough data at this point to be able to show that the new regimen in the doses are are safe and while we have in dosing patients at two Mig it would give us an opportunity then to.

Bring the higher dosing in that we're using ex U S.

The other part we would align for individuals who happened to be at lower doses, whether in the U S or outside the U S.

A dose was determined that need to be higher we will we will provide a makeup dose to those patients that will help bring their load level up in line with the other patients who will get them, where they need to be.

Now, with regard to the opt-in...

We will take the day to them and get to the U S. Open we believe with that ex U S data and get everyone aligned in phase III from there going forward in phase III, then we'd have the world or.

They're all regions aligned on a single phase III program.

The opt-in just gives us an opportunity to execute earlier on interim data, and it just gives an opportunity to potentially accelerate the program.

So let's talk about the crispy the cadence of growth as.

The decision on efficacy doesn't indicate that we would need more or better or worse efficacy. It's just an option for us, based on the interim data, to execute the acquisition earlier.

Under a different somewhat different set of terms, but we think it's a it's a potential way for us to accelerate the program depending on what we see and announce mid-year.

Thank you.

Some of it has been moving toward adults with Eric maybe you can provide a little more color on the growth and Christy that overtime.

Thank you.

Our next question comes from Yigal Nochomovitz with Citigroup.

This might not be related to our call.

So as far as per suite is concerned we're expecting to the steady growth in North America as we've seen and.

Okay, I won't.

We've been building momentum in Latin America for the last couple of quarters.

We expect that to continue to accelerate.

Although it is.

As we stated the growth.

We'll move on to the next question.

It was recognized in.

Tazeen Ahmad with Bank of America.

Stages, it was kind of lumpy in how it grows from quarter to quarter, but overall on an annual basis, it should be steady accelerating growth.

And then when you look at Europe .

We're seeing increase we're seeing steady sales growth and.

Named patient sales for <unk>.

The jewelry with some expansion across Europe for named patient sales with Adobe.

And I expect some meaningful start to recognize meaningful growth.

<unk> revenue in 2023 and beyond.

Thanks for taking my questions.

Thanks, Eric I think.

Emil, I just wanted to get a sense from you on how you plan on aligning protocols going forward between FDA and EU regulators, assuming that you're going to move into your pivotal study for Angelman.

In the U S. I think one of the elements of color that.

We can provide here is that there is a continuing shift to more adult patients and pediatric patients.

And that.

Nearly half the scripts are prescriptions. The new star forms are are coming from new prescribers with new paint new adult patients. So.

And then secondly, can you just talk about the cadence of growth for CRISPIDA thus far, it's starting to move into sort of the mid stage of growth, you know, what was the main growth driver this quarter?

There is a very broad diverse group of doctors out there who are treating patients and thats by.

By seeking and finding those patients will continue to find pages. When we find them. We have a very high rate of conversion to people, who actually want to prescribe. So it's about getting the word out and so thats.

Yeah.

<unk> to be a driver of steady growth is finding those new doctors new patients in the U S and we'll continue driving that activity.

Hopefully that's good for <unk>.

Yes.

Hello.

And where do you see the remaining opportunity for growth on a go forward basis?

Thank you. Our next question comes from Yaron Werber with Cowen.

Thank you.

Hi, This is brendon on for you around thanks for taking my questions guys. Just a couple of quick ones from us.

Good.

Chris I wanted to ask actually about the OTC pivotal study.

I just wanted to see what you can tell us maybe about enrollment and recruitment there I know originally.

Well, I'll deal with the protocol piece first, and Eric, maybe you can talk about the areas of growth for CRISPR after I finish with the first part.

Are they going to get underway earlier this year now looks like it's going to be closer to starting screening mid year. So just wanted to see if there's any color you can provide.

We are also planning to initiate an additional study in children less than five years old in the second half of the year.

And then on the Angelman, assuming a mid year update really focuses on the ex U S study.

The U S kind of get going here.

Do you have a sense of maybe the timing over the next six to 12 months of your planned cadence for additional updates from potentially higher doses.

Good so the OTC program among the three gene therapy programs, we had set the <unk> 401 for GSD <unk> is kind of our priority. There are a lot of patient ready, we were able to get through the process a little faster.

Driving that one ahead, which is now enrolling we purposely then put the OTC program a little further behind remember we're running four pivotal programs at once which is a lot for any company. So the OTC.

By design.

Behind it has not started enrolling but the sites are getting started and.

We've gotten through the process and regular regulatory process. So I think we're aligned up to go ahead and.

So on aligning protocols, it's not actually that difficult.

Both protocols are treating.

We will start enrolling and I think we'll do fine.

<unk> hundred one clearly we will I think be the first gene therapy to get through the phase III processing yield data.

GTX-102, the ASO in development with our collaborator Genetics for patients with Angelman syndrome, continues to dose patients under the amended Phase 1-2 protocol. In the UK and Canada, both Cohorts 4 and 5 have expanded following a review of available safety data by their respective DSMBs. We began dosing patients in December, with some receiving up to five doses so far.

Now with regard to Angelman.

This is essentially a once a month, but it's just a different dose and regimen for administration.

Right now we are coming up mid year with the current dose regimen, what we said in the past is that we would expect to take what we've learned and what doses, we've cleared and initiate new cohort starting at those new doses. So we can load patients.

So our expectation to align them is in, we'll align them in the phase two, we'll take our data from XUS, from Canada and the UK that show us that the drug is safe, and that the new administration strategy is appropriate, and bring that data, along with other safety data we have, to the U.S. and request that they open, essentially, an amendment that will align all three regions under the same protocol.

We think we have enough data at this point to be able to show that the new regimen and the doses are safe.

And while we have been dosing patients at 2 MIG, it would give us an opportunity, then, to bring the higher dosing in that we're using, XUS.

At the higher doses that have been cleared as safe.

And we would expect to be doing that this year. If we then are able to show that that dose is safe and reaches.

Our achieving a threshold across the patients that we would then expand it to a larger cohort of patients to collect more data while that larger cohort be enrolling later this year. We would then be beginning the process of planning and discussing regulatory authority of the phase III.

So the phase III would be expect to be something where we start next year.

That gives you a little more color on the timeline.

Yeah, that's great thanks very much.

Thank you. Our next question comes from <unk> <unk> with J P. Morgan.

Hi, This is Tiffany answer Cory.

So at this stage.

I guess, how many patients you can expect initial safety and efficacy data for him.

It will be our update and what would be the cutoff share inclusion there would it be simply any data ahead of that.

If I gave before that readout are kind of a required follow up is there anything at this time.

Well, the other part we would align is for individuals who happen to be at lower doses, whether in the U.S. or outside the U.S., if a dose was determined that needed to be higher, we'll provide a make-up dose to those patients that will help bring their load level up in line with the other patients, so we'll get them where they need to be.

Well, we would expect since we said that all eight patients in U S were enrolled.

We look forward to providing a more robust update on this program in mid-2022.

Four patients dosed at the <unk> dose level.

We would expect to provide all the data we have on them at that point in time.

Though we certainly be a certain amount of formal data, but we will provide what we know about how the patients are doing at that time to give people more of an interim look remember this is not a final end of the story study.

Update is just an interim look so we'll provide as much as we can on four patients that will have received multiple doses of <unk> as well as then the patients ex U S. In cohorts four and five I would've gotten the higher doses and been going through the titration.

So we'll take the data then and get the U.S. open, we believe, with that ex-U.S. data and get everyone aligned in Phase 2.

From there, going forward in Phase 3, then we'd have all regions aligned on a single Phase 3 program.

Got it.

Like 16 patients.

So let's talk about the CRISPR-Vita cadence of growth.

Yes, well, where we've enrolled GOR and five and the four yes.

Great. Thanks.

As you know, some of it's been moving toward adults, but Eric, maybe you can provide a little more color on the growth in CRISPR-Vita over time.

With these updates, I will now turn back the call to Emil.

Thank you. Our next question comes from Yigal <unk> from Citigroup.

Yeah, so as far as PRISFIT is concerned, we're expecting to steady growth in in North America, as we've seen.

Thank you.

Hi team. Thank you very very much for taking our questions apologies for earlier I was juggling multiple calls.

Thank you, Camille.

Just a question on the guidance for Chris Vita in the territories. So as far as I understand you did $55 5 million and <unk> 21 54, 6%.

The most recent quarter.

So just if you could just help elaborate a little bit on the rationale behind the $2 50 to $2 60, just because based on the last two quarters. It does seem perhaps a touch aggressive thank you.

Before we shift to the Q&A portion of the call, I'll provide a quick reminder of the key upcoming milestones for the company.

Yes, well, we have some experience now we're a bit of time on the program. So we're we're actually comfortable with how it performed and how the second half year is stronger and maybe Eric do you want to touch on that our marni.

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

Across the gene therapy pipeline, we'll continue enrolling the Phase 3 for DTX401 and the Phase 1, 2, 3 for UX701.

We also expect to finalize study... Study Startup Activities for DTX-301 and begin dosing patients in mid-2022.

On the manufacturing side, we will continue to build out our facility at Bedford, Massachusetts, which is on track to begin producing material next year.

Eric.

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

And, you know, we've been building momentum in Latin America for the last couple of quarters.

All these programs create a distinct opportunity to make a meaningful difference for patients with a rare genetic disease.

We look forward to sharing further updates with you throughout the year.

Yes, so with regards to the steady growth in North America, we're seeing accelerating growth in Latam.

You also may have seen that we have launched our inaugural ESG report for 2021 last month.

This report is a meaningful evolution of the journey we've been on for the last 12 years as a company.

We'll continue to build on this foundation and report on our progress.

And expecting.

<unk> full reimbursement by the end of end of the year, which will help speed up the.

Transitioning patients that have been waiting for.

Treatment through the injunction process of named patient sales process.

So Latin America will contribute did you want to add I was just going to add you got if you look at the quarterly progression in 'twenty one.

We expect that to continue to accelerate in growth, although it, you know, as we stated, the growth, is recognized in stages. It's kind of lumpy in how it grows from quarter to quarter.

In terms of how the sales progress throughout the year, we expect the same in 2022 as well.

But overall, on an annual basis, it should be steady, accelerating growth.

First quarter is always has seasonality impact in the prion work et cetera, and then there's just some timing between Q4 and Q1, but you should see in the second half of the year that the revenue is concerned yes continue.

Continued to accelerate.

Yes, we feel we feel good about the guidance range of $2 52.

So we're reconfirming that today.

Yes.

Thank you Rob pattern seasonal pattern plus improvement in Latin America, we feel good about what Christy is continuing to grow.

Demand is strong and the.

Compliance or persistence has been excellent so people once they get on they really do see on the right.

Probably as good as they've ever seen so we're we think it's a great product we will continue to grow.

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

Alright, Okay next question.

Operator, please provide the Q&A instructions.

Oh can I ask another one.

Oh.

Go ahead.

Thank you.

Okay.

As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key.

Okay.

We ask that you limit your questions to one question and one follow-up.

Please stand by while we compile the Q&A roster.

And then hopefully this wasn't already asked but in terms of just the quarter over quarter trends for North America, and assuming that the $45 million.

Our first question comes from Gena Wang with Barclays.

Thank you for taking my questions.

This most recent quarter was a seasonal effect.

I have two questions on Andrew Mann's program.

And then if you could just comment on rest of world look very very nice increase quarter over quarter. So if you could just comment a little bit.

So, Emil, maybe can you comment on any chemistry differences between your log nuclear acid versus Roche's log nuclear acid?

The thinking behind that.

Yeah well.

Thank you, Gena.

Let me be Eric do you want to talk to the car on quarter thing I think it's kind of reordering, we just went through.

Consistent with Marty will just statements was weak the first quarter was pretty much in line with our expectations.

We had anticipated some seasonality as you stated as a result of the re optimization process.

In addition.

The omicron virus impacted us a bit more than it had been.

Covid impacted as previously as we have.

Three quarters of our sales force out on protocol at some point in the first two months of the year.

So there was some impact there but.

Consistent with previous years, we are expecting steady growth throughout the year with quarterly splits.

Consistent with what you saw in 2021 with.

Increasing sales in the second half of the year.

And with regards to the rest of the world.

That statement, increasing momentum in Latin America is more and more patients are.

Being granted injunctions and receiving reimbursed therapy.

And thats going to continue to accelerate as we get.

Full reimbursement.

In Brazil and across other countries in Latin America.

And then when you look at Europe.

Then with regards to Europe .

But we've seen steady growth.

And named patient sales with the jewelry, particularly driven by France, and Italy, and now we're expanding that across other countries.

And in Europe .

And subsequently.

The potential for.

You know, we're seeing increased, We're seeing steady sales growth in named patient sales for the Jovi with some expansion across Europe for named patient sales for the Jovi and expect some meaningful, start to recognize meaningful growth of FTSA revenue in 2023 and beyond.

Meaningful increasing revenue in 2023 with <unk> CAGR.

Thanks, Erik.

In the U.S., I think one of the elements of color that we can provide here is that there is a continuing shift to more adult patients and pediatric patients and, and that, Nearly half the scripts or prescriptions, the new star forms are coming from new prescribers with new adult patients.

There's a very broad, diverse group of doctors out there who are treating patients, and that's by seeking and finding those patients.

Good.

Answer your question, let's go onto the next question, yes, thanks for color.

Thank you.

Thank you and next we have joon Lee with true security.

We'll continue to find patients.

So, on the chemistry differences, I'm not deeply familiar with the specifics of the Roche molecule and all the different linkages, because there are a lot of linkages.

Hi, Thanks for taking our question.

When we find them, we have a very high rate of conversion to people who actually want to be prescribed, so it's about getting the word out.

We know that it has locteic acid, Gatmer, like ours is.

And so that's, Continuing to be a driver of steady growth is finding those new doctors, new patients in the U.S. and we'll continue driving that activity.

There are some specific differences on the sequence, no doubt, and some other minor chemistry changes.

Hopefully that's good for you, Tazeen.

But I think the biggest change is differences between where these are targeted.

In the prepared remarks regarding Gtx 102, you mentioned enrolling in drug and a comparator group can you elaborate on what you mean by the comparator group and also you said you have administered up to five doses. Some patients are you able to share that same cohort four.

Yeah, that's good.

Thanks, Emil.

And the overall safety profile of a product, it's not just the chemistry. It's also the dose and the potency that will determine it.

And we believe, based where ours is targeted, it is very potent and that the dose range will be at a lower end of the range, which is partly related to the potency of the locteic acid type of ASO.

So we're confident about the chemistry we have.

And while they both have LNA locteic acid components, I can't say that you can make any conclusions from those differences alone.

Now, with regard to the opt-in. The opt-in just gives us an opportunity to execute earlier on interim data, and it just gives an opportunity to potentially accelerate the program.

The decision on efficacy doesn't indicate that we would need more or better or worse efficacy. It's just an option for us, based on the interim data, to execute the acquisition earlier. Under a somewhat different set of terms, but we think it's a potential way for us to accelerate the program depending on what we see and announce mid-year.

Thank you.

Or in the U S. Thank you.

Our next question comes from Yigal Nochomovitz with Citigroup.

This might not be related to our call.

So in the U S with the FDA agreement that we're going to dose we dosed four patients with two migs once per month that was the agreement.

Okay, I won't.

We'll move on to the next question.

Tazeen Ahmad with Bank of America.

Hi, okay, thanks for taking my questions.

Emil, I just wanted to get a sense from you on how you plan on aligning protocols going forward between FDA and EU regulators, assuming that you're going to move into your pivotal study for Angelman.

They also want us to enroll another four patients.

And then secondly, can you just talk about the cadence of growth for CRISPIDA thus far?

It's starting to move into sort of the mid-stage of growth.

You know, what was the main growth driver this quarter, and where do you see the remaining opportunity for growth on a go-forward basis?

Not randomized and another for patients to be enrolled is simply just do the assessments on them without drove the drug dosing alright.

Yeah.

So thats a for a comparator that was described before but perhaps.

<unk> got missed so thats, what's happening ex U S. The question on up to five we're talking about the patients now ex U S.

And so the first few patients have actually gotten all four doses with one maintenance dose.

Alright, so its five doses and others have less lesser numbers, we haven't put out the specifics of all of the time course of all of it but.

The point would be that we have now multiple patients who've gotten.

Five doses of drug.

Without any lower extremity weakness so just to clarify the issue that simply exposing the patient of the drug repeatedly is not going to cause the problem by itself at any dose level.

Sure.

Quantify whats the rationale for having a comparator that is not a placebo.

I don't understand.

Well I think they wanted to kind of look like.

Well you want me to read the Fda's mind the FDA.

Does looking knowing that a placebo is hard to do I think what they are looking for is some measure of how consistent you would do that you would do these complex psychologists driven tests on a patient and how what that would look like just to understand the variability of the methods when theyre done repeated.

Lee.

The basis for it it's not a true control I think they just wanted to look at how much variation would you see.

Just in measuring patients with the people doing it.

So it's a test of the system really and not really a control group in that sense and it's fine I think what we're confident is the patients don't really change much.

But there's no doubt when you do measures like this there's going to be some variation.

Question is whether what we see in our patients is beyond variation and we've addressed that before to say that the magnitude of change seen for example in the Vineland score that was presented last year at fast showed the level of change observed was far beyond what you would see in placebo change overtime or control group for natural history.

So we're comfortable with that is what that four patients or four and we are complying with the fda's request on just having for more patients getting assessed.

Thank you.

Thank you. Thank you okay.

Let's move on.

Our next question comes from Yaron Werber with Cohen.

Good.

Thank you. The next question comes from Joseph Joseph Schwartz with SBB Securities.

Hi, this is Brendan on for your own.

Well, I'll deal with the protocol piece first, and Eric, maybe you can talk about the areas of growth for CRISPFEDA after I finish with the first part.

Hi, Andrew dialing in for Joe. Thank you for taking our questions.

Thanks for taking the questions guys.

So on aligning protocols, it's not actually that difficult.

You previously mentioned using a multi domain responder index as a possible endpoint for Gtx one two so curious what the receptivity issue that endpoint some of the regular regulatory agencies in phase III and then secondly are there other domains you would consider for the MRI. Besides the five and the CGI.

Both protocols are treating.

This is essentially a once a month, but it's just a different dose and regimen for administration.

So our expectation to align them is in, we'll align them in the phase two, we'll take our data from XUS, from Canada and the UK that show us that the drug is safe, and that the new administration strategy is appropriate, and bring that data along with the other safety data we have to the U.S. and request that they open essentially an amendment that will align all three regions under the same protocol.

We think we have enough data at this point to be able to show that the new regimen and the doses are safe.

And while we have been dosing patients at 2 MIG, it would give us an opportunity then to bring the higher dosing in that we're using, XUS.

So, we'll take the data then and get the U.S. open, we believe, with that ex-U.S. data and get everyone aligned in Phase 2.

Just a couple quick ones from us.

From there, going forward in Phase 3, then we'd have all regions align on a single Phase 3 program.

First I wanted to ask actually about the OTC pivotal study.

So let's talk about the CRISPR-Vita cadence of growth.

I just wanted to see what you can tell us maybe about enrollment and recruitment there.

As you know, some of it's been moving toward adults, but Eric, maybe you can provide a little more color on the growth in CRISPR-Vita over time.

I know originally this was thinking to get underway earlier this year and now looks like it's going to be closer to starting screening mid-year.

Yeah, so as far as Christopher is concerned, we're expecting to steady growth in in North America, as we've seen.

And, you know, we've been building momentum in Latin America for the last couple of quarters.

We expect that to continue to accelerate in growth, although it, you know, as we stated, the growth, is recognized in stages. It's kind of lumpy in how it grows from quarter to quarter.

And then when you're looking at Europe.

But overall, on an annual basis, it should be steady, accelerating growth.

You know, we're seeing increased, We're seeing steady sales growth in named patient sales for the JOVI with some expansion across Europe for named patient sales for the JOVI and expect some meaningful, start to recognize meaningful growth of FQISA revenue in 2023 and beyond.

Hi.

And do you know what the minimally important differences are for the individual domain does that.

Professional can be considered a responder. Thank you.

Well this is a deep dive into the clinical study design very good. Thank you.

So just wanted to see if there's any color you could provide.

Thanks, Erik.

And then on Angelman, assuming the mid-year update really focuses on the ex-US studies as the US kind of gets going here, do you have a sense of maybe a timing over the next 6 to 12 months of your planned cadence for additional updates from potentially higher doses?

In the U.S., I think one of the elements of color that we can provide here is that there is a continuing shift to more adult patients and pediatric patients and, and that, Nearly half the scripts or prescriptions, the new star forms, are coming from new prescribers with new adult patients.

For those who don't know what the multi domain responder rates as it's a technique for just analyzing endpoint that allows you to capture the totality of the data across multiple domains.

Good.

There's a very broad, diverse group of doctors out there who are treating patients, and that's by seeking and finding those patients.

So, the OTC program, among the three gene therapy programs, we had set the DTX401 for GST1A as kind of our priority. There were a lot of patients ready. We were able to get through the process a little faster.

We'll continue to find patients.

And driving that one ahead, which is now enrolling, we purposely then put the OTC program a little further behind.

When we find them, we have a very high rate of conversion to people who actually want to be prescribed, so it's about getting the word out.

Remember, we're running four PIVLs programs at once, which is a lot for any company.

And so that's, Continuing to be a driver of steady growth is finding those new doctors, new patients in the U.S. and we'll continue driving that activity.

So, the OTC is, by design, a little bit behind.

Hopefully that's good for you, Tazeen.

Yeah, that's good.

Thanks, Emil.

Thank you.

We are in a paper on it with our head of biometrics PK tendon and we've also had meetings with the FDA, including a large number of senior FDA people about the meaning of the approach. They are interested in it they have questions still but it needs kind of a test case and perhaps angelman is the test case. It has not been accepted yet although it was.

It has not started enrolling.

But the sites are getting started, and we've gotten through the regulatory process.

So, I think we're lined up to go ahead, and we'll start enrolling, and I think we'll do fine.

DTX-401 clearly will, I think, be the first gene therapy to get through the phase three process and yield data.

Except in the sense that we ran in <unk> in our <unk> program that was approved it did hit the endpoint and the small study showing the power of the MRI to capture efficacy.

Now, with regard to Angeman...

Right now, we're coming out mid-year with the current dose regimen. What we said in the past is that we would expect to take what we've learned and what doses we've cleared and initiate new cohorts starting at those new doses so we can load patients at the higher doses that have been cleared as safe, and we would expect to be doing that this year.

If we then are able to show that that dose is safe and reaches our achieving threshold across patients, that we would then expand it to a larger cohort of patients to collect more data.

While that larger cohort would be enrolling later this year, we would then be beginning the process of planning and discussing regulatory authorities of the phase three.

And so the phase three would be expected to be something we'd start next year, that give you a little more color on the timeline then.

Yeah, that's great.

Thanks very much, Emil.

Thank you.

If we were to approach it in Angelman syndrome, we would the 5% means we're talking about are probably the ones. We would pick the seizure domain because they are on seizure meds and they've all been in control there's not much power there if they ever having a lot of seizure that could be also a domain, but I think the other domain, we would use our.

Basically the communication domain receptive and expressive as well as sleep behavior, which basically through the Vineland and we would also look at.

<unk> motor and gross motor scale for each of those scales like the Bally's for express communication and I'm fine motor motor those tools have normative data as well as what are considered.

Data to support them not necessarily in Angelman syndrome, but in general and so we think theres a lot of those types of them are thresholds that we could capture I have we have an entire team head by Alexandra was terrific at this stuff and they can generate more mid's or supportive data, but we feel like it's a very powerful way.

<unk> to look at heterogeneous complex diseases like <unk> that said, if we had to we could do CGI, we see tremendous power in the CGI and the FDA has accepted before so I don't see any risk here with you one or the other we can always put them to rise of secondary and gain the benefit of it there if we get approved off.

A primary CGI Angelman syndrome. So at this point I feel like the good part is we're talking about magnitude of changes there are meaningful easily captured and therefore, you can do it practically anyway, you want too and that will work.

Okay, great. Thank you very much.

Our next question comes from Iori Kazimoff with J.P. Morgan.

Our next question comes from Yaron Werber with Cohen.

Thank you. Our next question comes from Maury Raycroft with Jefferies.

Hi, this is Tiffany.

Hi, this is Brendan on for your own.

Hi, Thanks for taking my question.

I'm for Corey.

Thanks for taking the questions guys.

I was going to ask a question about Angelman safety. So based on the time course of the SAE near original patient number to disclose previously it appears to be a peak dose it back, but how do you get comfortable with cumulative dosing effects since the assay occurred about $6 30 days after the last dose across the five patients.

So at this stage with Angelman, do you have any idea of how many US patients we can expect initial safety and efficacy data from at the mid-year update?

Just a couple quick ones from us.

And what would be the cutoff for inclusion there?

Would it be, you know, simply any data ahead of a specified date before the readout or kind of a required follow up through a certain amount of time?

Well, we would expect, since we said that all eight patients in the U.S. were enrolled, and Fork Patients Dosed at the 2Mg dose level.

Well the reason, we get comfort that it's not accumulative because the actual dose chemo dose that was someone had the problem with highly variable between patients and unrelated to the severity.

You know, we would expect to provide all the data we have on them at that point in time.

There will certainly be a certain amount of formal data, but we would provide what we know about how the patients are doing at that time to give people more of an interim look.

Remember, this is not a final end-of-the-story study update.

It's just an interim look.

So we'll provide as much as we can on four patients that will have received multiple doses of TUG, as well as then the patients XUS and Cohorts 4 and 5 that would have gotten the higher doses and been going through the titration.

Got it.

One patient the fifth patient at one dose only 20 and had the effect. We had also the first patient that had.

So it's sort of like 16 patients.

106 milligrams.

And had mild mild problem so.

There is not much relationship to the accumulation and the time course of effect like the six days or so.

The time course of these adverse effects doesn't fit the efficacy effect. So this has nothing to do with the drug acting as an ASO in the brain tissue has to do with an effect that is very local.

Something irritating.

Irritating the.

The nerves there right. So it is really something operating on a different time course different mechanism and everything we have says.

A concentration dependent effect.

And what we're seeing right now dosing for as many months as we have and we're not seeing the effect of accumulation, causing a problem right. Marty. So that was your question was why.

While we told you we don't know multiple patients have given five doses over a months right and not seeing the effects of accumulation would've done. It then they would have had a problem, but they haven't so.

It verifies our view that this is an acute toxic kind of effect of due to high concentration, it's more like an irritation of the <unk> and the nerve roots and.

And we think that the changed administration method dosing administration method are going to mitigate that and we think we've seen that that's true.

Got it Okay. That's really helpful. Thanks for taking my question.

Sure.

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

First I wanted to ask actually about the OTC pivotal study.

Hi, This is Tommy on for Celgene, Thanks for taking our question.

I just wanted to see what you can tell us maybe about enrollment and recruitment there.

Wanted to follow up about Angel and safety.

Please limit your confidence on why the Ftes were doses I think rather than molecule statistics, specifically as it relates to like the chemistry and the binding site.

And then.

An update maybe on where you're at now is dose escalation what level you think could be reached by the by the update thank you.

Sure. So thanks for your question I think youre, asking whether the safety effect was related to the molecule versus the chemistry.

I think from the safety work done on the molecule, meaning the sequence itself.

We're comfortable that it's not hitting.

Site target effects in other situations. When you look at the pattern of the safety effect. The fact that peaks in a week or two and then declining over several weeks it doesn't fit the specific antisense oligonucleotides pattern of its concentration and presence at <unk>.

It's a different kind of thing what we do now and it's been published that ASO is in general have enough specific chemistry toxicity kind of thing that we demonstrated in vitro. If you put a lot of it in there. It goes in will bind certain proteins in cars.

Some toxicities in so this tells you just have to manage the local concentration carefully at the time, we administered that chemistry that can be enhanced by being a lock nucleic acid, but then the locked it take us. It also gives you longer half life and greater potency.

So the question is how do you balance those.

<unk> of Lark to click asset versus the toxicity issues I think there are ways to look at that and we think with the molecule. We have we're targeting and the fact that.

Only one milligram in a monkey can provide.

Efficient knockdown, which is well below what's been seen with ourselves. We think we have the level of potency that the benefit of <unk> can be obtained without.

Risking.

<unk> issue that happened from those more stable end.

Type of ASO.

Thanks, and then just.

Follow up on the dose escalation.

Progress there.

Yeah, well, we've enrolled the Corps in five and then the four, yes.

Well as we've said we have.

Several patients have gone through five doses, which means they have gone through the four doses and have gone into maintenance, we havent really disclosed all of the levels of dose titration, there hasnt titration.

And we will put out all of that detail on <unk>.

I know originally this was thinking to get underway earlier this year and now looks like it's going to be closer to starting screening mid-year.

Creation of what dose level and outcomes and all the patients at the mid year, it's not really appropriate to start putting that out yet but.

So just wanted to see if there's any color you could provide.

As Ive said multiple patients have reached five which means they had for loading doses and then one dose.

Of their maintenance regimen, which have three months after the fourth dose.

Okay, great.

Thank you.

Thank you. Our next question comes from David <unk> with Stifel.

Our next question comes from Yigal Nochomovitz from Citigroup.

Doug are you there.

Hi, I'm Mill and team.

Operator, why don't we move to the next question.

Thank you very, very much for taking the questions.

Our next question comes from Jeff Hung with Morgan Stanley .

Apologies for earlier, I was juggling multiple calls.

Thanks for taking my question can you talk about what we should expect to see from US is truth I Mab in the U S. So five three updates later this year.

Just a question on the guidance for Chris Avita and the Ultragenyx territories.

Good.

Sure so in <unk>.

We expect to have.

We purposely then put the OTC program a little further behind.

Almost 40 patients enrolled little gotten two months of dosing and what we'll have is information on their biomarker. The <unk> borrowing biomarker, which were based on the historical data from the asteroid steady 90 patients.

Remember, we're running four PIVLs programs at once, which is a lot for any company.

So, the OTC is, by design, a little bit behind.

It has not started enrolling, but the sites are getting started, and we've gotten through the regulatory process. So, I think we're lined up to go ahead, and we'll start enrolling, and I think we'll do fine.

A nice correlation between their bone marrow density improvements.

That and the <unk> MP. So we will look at the <unk> marker and other data safety efficacy and to help make a decision we'd put out what our decision is on the dosing algorithms for pediatric and adult patients in the disease. So you'll learn about safety biomarker information at a high level and then we.

So as far as I understand, you did 55.5 million in 4Q21, 54.6 in the most recent quarter.

DTX-401 clearly will, I think, be the first gene therapy to get through the phase 3 process and yield data.

Now, with regard to Angeman...

So if you could just help elaborate a little bit on the rationale behind the 250 to 260, just because based on the last two quarters, it does seem perhaps a touch aggressive.

Thank you.

We'll talk about what our dosing strategy going forward in our plan to start phase III, that's the truth.

<unk> three we're going to have basically single dose ascending ascending dose data in which we'll look at.

Safety of course, and as well as effects on glucose and other biomarkers and clinical.

If we then are able to show that that dose is safe and reaches our achieving threshold across patients, that we would then expand it to a larger cohort of patients to collect more data.

Thanks very much, Emil.

While that larger cohort be enrolling later this year, we would then be beginning the process of planning and discussing regulatory authorities of phase three.

And so the phase three would be expected to be something we'd start next year, that give you a little more color on the timeline then.

Assessments as well.

Yeah, that's great.

But because it's early and it's only single dose we wouldn't expect to see dramatic clinical benefit at this point, but we're looking to see clinical activity and the biomarkers endpoints that would help us assess it.

Yeah, well, we have some experience now or a bit of time on the program.

So we're, we're actually comfortable with how it performs and how the second half year is stronger.

Enzyme being delivered as being the RMR RNA being liberty's being translated the enzyme is active and is doing what it needs to do in the liver.

Okay.

And maybe Eric, do you want to touch on that or Marty?

Thank you.

The next question comes from Joel Beatty with Baird.

Eric?

Our next question comes from Yori Kazimoff with J.P. Morgan.

Alright, thanks for taking the question.

Thanks, Chris.

Yeah, so with regards to the steady growth in North America, you know, we're seeing an accelerating growth in LITAM, I'm expecting a potential full reimbursement by the end of end of the year, which will help speed up the transition to patients that have been waiting for treatment, through the injunction process, named patient sales process.

Hi, this is Tiffany.

So Latin America will contribute, did you want to add something?

I'm for Corey.

Once patients starting therapy.

And then sticking on therapy have you seen any drop off there.

I was just going to add, Yigal, if you look at the quarterly progression in 2021, you know, in terms of how the sales progress throughout the year, we expect the same in 2022 as well.

So at this stage with Angelman, do you have any idea of how many US patients we can expect initial safety and efficacy data from at the mid-year update?

So you're going to see, you know, first quarters always has seasonality impact and the pre-op work, et cetera.

And what would be the cutoff for inclusion there?

Then also for gene therapy manufacturing once the plant is operational next year, how does the capacity of that plant comes here too.

And then there's just some timing between Q4 and Q1, but you should see in the second half of the year that the revenues continue to accelerate.

Would it be, you know, simply any data ahead of a specified date before the readout or kind of a required follow up through a certain amount of time?

So, yeah, we feel we feel good about the guidance range of 250 to 260.

Well, we would expect, since we said that all eight patients in the U.S. were enrolled, and 4 patients dosed at the 2 mg dose level.

You know, we would expect to provide all the data we have on them at that point in time.

There will certainly be a certain amount of formal data, but we would provide what we know about how the patients are doing at that time to give people more of an interim look.

Remember, this is not a final end-of-the-story study update.

Our next question comes from Yigal Nochomovitz from Citigroup.

It's just an interim look.

Hi, I'm Milton Thiem.

So we'll provide as much as we can on the four patients that will have received multiple doses of TUG, as well as then the patients XUS and Cohorts 4 and 5 that would have gotten the higher doses and been going through the titration, got it to a total of like 16 patients.

Yeah, well, we've enrolled the Corps in five and then the four, yes.

Okay, great.

Thank you.

Clinical pipeline programs you have in development.

Okay. So the persistence or compliance Youre talking about was for Christina.

Yes.

Okay.

Chris Vida is in the.

Chris fee that persistence is is in the high 90 percentile range. So it's quite excellent and.

And compliance is in the 90% plus range so.

We see these are really good numbers for compliance and persistence so far.

I think part of the reason for that is patients can feel when they're on the drug and when they are not on the drugs if they miss a dose.

The phosphate will start to fall and they'll feel that effect of that and that just tells you need to get back on so we think that the fact that they can feel when their phosphate goes down it's probably a factor in why theyre staying compliant and once they get on they want to stay on.

So thats.

That.

Gene therapy plant.

100000 square foot plan it will have ultimately two suites independents.

Independent suites that can run up to 2000 liter production.

And we will turn out can turn over a number of runs of the year. It should be able to handle a significant fraction of our total though where plan was still to use a hybrid model with some contract manufacturing to supplement it.

If we hit our marks and we get where we want to be.

Commercializing gene therapy, we have also the ability we have additional land that we have purchased next to the plan that we can add essentially double the plant up with two more suites that could make double the total capacity so with.

Within those range, we would have a good fraction of what we're doing on but we still are planning a hybrid model not a complete takeover of manufacturing.

If time goes push comes to shove, we need to we certainly would have the capacity ultimately to take on the programs. We have short of Duchenne, if the Duchenne program does well hit the clinic.

Lottery product required for that program will be substantial and we will need more capacity.

Great. Thank you.

So we're reconfirming that today.

Our next question comes from Laura Chico with Wedbush.

Yep, seasonal pattern plus improvement in Latin America.

Thank you very, very much for taking the questions.

Thanks, very much for taking the question.

I guess I wanted to take a step back and.

For Amarin team.

How should we be thinking about the potential for longer term revenue guidance targets. Obviously casita you have considerable experience with this but youre approaching a transition point.

Just kind of wondering.

Apologies for earlier, I was juggling multiple calls.

What is the potential for longer range targets, and then maybe secondarily, how do you balance becoming profitable with continuing to expand your pipeline of parts at this point. So thank you very much.

We feel good about what Christie is continuing to grow and I think the demand is strong and the, Clients and persistence has been excellent.

Just a question on the guidance for Chris Avita and the Ultragenyx territories.

Thank you Laura first of all I think our.

So people, once they get on, they really do stay on the sprout, probably as good as any we've ever seen.

<unk> is the steady growth and the addition of the pieces to help also fill out the pipeline growth, but Christy that we will be continuing to grow we believe along with <unk>, which is doing really well that puts us on track with the three product and now adding its chiesa hit.

Substantial revenue growth every year in the in the.

<unk>.

30, plus percent range or more.

So we're, we think it's a great product will continue to grow.

So as far as I understand, you did 55.5 million in 4Q21, 54.6 in the most recent quarter.

So we feel very good about where that's taking us now with regard to our pipeline.

All right.

So if you could just help elaborate a little bit on the rationale behind the 250 to 260, just because based on the last two quarters, it does seem perhaps a touch aggressive.

Okay.

Thank you.

Our plan here was not to run which run about 68 clinical stage programs at the same time Lora and then not to grow beyond that to be able to run 68 clinical stage once they become commercial it separate but the.

Next question.

Oh, can I ask another one?

Yeah, well, we have some experience now or a bit of time on the program. So we're, we're actually comfortable with how it performs and how the second half of the year is stronger.

In development stage 68, the idea is that we want to create a certain size of spend around R&D that would generate a product filing a on an average every year. If you average it over two or three years and we think that's when we can do it. So we don't want to keep growing R&D and definitely we are growing into the size.

We are at a peak right now because we have four programs in pivotal which is not normal and.

What our expectation is that over the next couple of years, we will start to plateau, and we will try to hold line there around that level of R&D spend and our expectation in the revenue continue to grow and we will get operating leverage in and go profitable and that is our plan.

Our plan, though when you go profitable to go profitable with a lot of products new products launching which we would expect in the next three or four years, which would put us in position to cross profitability.

Not profit, but to really fly far above it so.

I think there's always a debate.

How much you want to spend versus how much you want to manage profitability. The key is when you spend to spend well.

And to spend smartly and effectively and Thats, what we focus a lot on but right now we think the level of spend we're at is around the range, we want to be in the long run and as long as we continue to grow our revenues, we can well had to be a profitable company in the picture we see in the long range plan shows a whole series of.

Generating revenue for us in a very robust diversified pipeline across mode, and therapeutic indication, which I think will make us.

One of the leading companies in the field of rare diseases.

Thanks, so much.

Thank you.

Thank you. Our next question comes from David <unk> with Stifel.

Great. Good afternoon, thanks for taking our questions and sorry about the earlier hiccup two questions from me one on Gtx 102, Amy I wanted to ask you about sort of the confidence in the strength and the Gtx 102, IP. It looks like there is a little bit of an overlap on the sequence targets that Roche.

<unk> genetics are all kind of going after so I wanted to get your take on that and secondly, following up on the previous question.

Going back to <unk>, you kind of prioritize a readily commercialize a bowl product but.

I guess going forward, what kind of directionality would be enticing to you is it more commercialized products or something like genetics, where you can take basically the entire ownership of a program. Thanks so much.

Okay.

With regard to the.

The Gtx one to IP there is a distinct region within the IP. The techs A&M has the genetics license that we licensed part of our deal that is distinctive and separate from where I owned and Roche operate distinct separate towards the five prime end of the MSS message.

The description we use involved.

That sequence plus we also are targeting not necessarily just introns, but conserve sequences and other aspects of what we do that are unique different which are important in achieving potency because the five prime and there is a lot more potent at terminating the transcription of the Anson RNA as well as destroying existing messages.

And Thats why we think that five prime in that is uniquely patented is powerful and important that is where the five prime end of the long end since message come from so that's why we think there is a separation of distinct <unk> why we did the deal originally because there's no way I would've planned to go head to head with Roche and Biogen ion.

As on a neurologic disease.

Except for the fact that the group had an edge and they wanted to work with us and it looks like an opportunity we should take.

So.

On the question of commercial versus.

Versus pipeline I think it is a fundamental question for you because I've had people say why don't you buy $1 billion product, that's commercial well, yes, but how much do you have to pay for $1 billion product to our commercial so obviously I don't think buying a product you know is building our products are already commercial is a good deal because I don't think theres any gain there is an arbitrage there is no way.

To make money as a company, we can't do that with the premium on paying for it and the rest.

So when we buy layers each commercial product they may be smaller niche products that are great for us where we can extract value with our unique.

Distribution system and team across the globe.

That is what regeneron wanted and we're able to use that skill to gain value from something with a $30 million upfront.

Now.

Angelman, we can't make build a company on the smaller product we need to have some larger return products. Those are going to have to be earlier stage program, where then we have to take our developmental insight and skill to Pic design drive and execute in a reasonable timeframe. It takes something of uncertain value and turn it into something of value.

And I think you would agree that a 'twenty owned our investment on a multibillion dollar opportunity that has now turned into.

Something of great value is the kind of investment we should be in as a biotech.

But adding a late stage commercial product that leverages, our operating revenue and takes advantage of our rare disease skills. Commercially is also a good deal. So if you see a late stage deals more likely to be smaller niche and perfect fit for us and if it's earlier stage, we might do some things that are higher risk higher return, but where we can.

Add value and grow the value through our particular skills.

Hopefully that gives you a kind of a feel for our view.

Yes. It does thank you very much.

Thank you. Our next question comes from Uganda, Gelowicz from Citigroup.

Hi, Thank you so much for taking the follow up just two clinical ones Aneel.

On the gene therapy programs I don't think I've ever asked you this before but could you just clarify.

Why for 401 and for 301, Youre doing a one to one randomization, but for Wilsons do op support two to one randomization. Thank you.

Yes, well in the.

301, a 401 originally we were going to do it.

Two to one and a 40 patient study and specifics.

Specifically decided we ought to go one to one to improve the power of the study and because I thought a 40 patient study with on the smaller side.

And the powering of the study is dependent on the size of the placebo arm and since we're looking at patients who are uncontrolled treatments.

We need to make sure we have an adequate power and so.

Hi.

Increasing and making one to one we're able to look at the existing treatment the others.

Now for the Wilson program, if you noticed the total size of the program with much larger right.

So there's 27 people in the first part.

<unk>.

Treated three placebo in each dose group 27 right.

Plus there will be $60 70 in the phase III part of the study so because the study is much larger we can afford to do the two to one randomization still have enough power remaining by a large enough placebo group and because it has really good biomarker essentially urinary copper accretion. These are things we can measure great rely.

Ability and so we think the two to one works or that it's nicer to patients and we think the Si largest size of the study which is enabled by our better PCL manufacturing platform.

Puts us in position to be able to do a study that will cost less to make but it will treat more patients.

Okay. That's very logical thanks, and then just one on <unk> I apologize. If this has already been asked but just with respect to.

Feeling comfortable moving into a phase III for <unk>.

Could you be a little more specific in terms of the point improvement you'd like to see in CGI.

And across a minimum number of domains. So if you could provide a little quantitative commentary on sort of what point improvement you need to see in and how many domains youre aiming for it to feel good about taking the phase III.

Well, we had described before that for the purpose of dose titration. We were looking at at least two domains of plus two are better plus do meaning much improved or very much improved in the prior program. We had three patients that were much improved or a plus 2%.

Two patients that were very much improved.

That gives you kind of a sense of what we might see but I would look at those as a trajectory amount of improvement over a period of time, the actual true differential efficacy might depend on how long, we decided that we'll monitor and treat them, but I think that that level of change suggests to us that.

Not long and essence message must be knocked down at UBS expression must be induced <unk> induced at maximally.

Doing it more doesn't matter you just need to give patients time to <unk> <unk>.

Develop and improve their skills. So we.

We are looking and if we were if we are running a study with CGI S. We'd want to see a plus two or better.

And our design for our phase III, that's what we'd want to see.

We wouldn't want to go with a program that was going to give you a plus one.

We'd want to make sure we get our K.

<unk> titration dosing such that we're looking at a much improved kind of score and I think patients deserve to have us do the work to make thats right I think it's within our grasp we know it can be achieved.

And we're close to where we need to be so I think it's achieved.

Achievable to get to that level of efficacy with this program.

Great. Thanks, so much.

Thank you I'm showing no further questions at this time I would now like to turn the conference back to Joshua <unk>.

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

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

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Go ahead.

Eric?

Okay.

Thank you.

You're on.

Today's conference is being recorded if you'd like to have assistance. During the conference. Please press Star Zero I would now like to hand, the conference over to your speaker today Joshua Hager.

Okay.

Yeah, so with regards to the steady growth in North America, you know, we're seeing an accelerating growth in LITAM, We are expecting potential full reimbursement by the end of the year which will help speed up the transition of patients that have been waiting for treatment, through the injunction process, named patient sales process.

Good afternoon, and welcome to the Ultra <unk> pharmaceutical financial results and corporate update conference call for the first quarter 2022, 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> director of Investor Relations. Joining me on this call are <unk> <unk>.

Executive Officer, and President, Eric Harris, Chief Commercial Officer, Mardi Dier, Chief Financial Officer, and Camille Bedrosian, Chief Medical Officer, I would like to remind everyone that during today's call. We will be making forward looking statements. These statements are subject to certain risks and uncertainties and our actual results may differ materially.

And then hopefully this wasn't already asked, but in terms of just the quarter over quarter trends for North America, I'm assuming that the 45 million in this most recent quarter was a seasonal effect.

So Latin America will contribute.

Please refer to the risk factors discussed in our latest SEC filings I'll now turn the call over to Amos.

Did you want to add something?

And then if you could just comment on the rest of the world, look, very, very nice increase quarter over quarter.

I was just going to add, Yigal, if you look at the quarterly progression in 21, you know, in terms of how the sales progress throughout the year, we expect the same in 2022 as well.

Thanks, Josh and good afternoon, everyone.

So if you could just comment a little bit on the thinking behind that.

So you're going to see, you know, first quarters always has seasonality impact and the pre-op work, et cetera.

In the first quarter, we continued to make progress across our diverse clinical and commercial programs and.

And then there's just some timing between Q4 and Q1.

In the late stage clinical pipeline, we're now enrolling patients in three Registrational studies with the fourth to initiate later this year.

This includes the three gene therapy programs for glycogen storage disease type one a.

Wilson disease in ornithine, <unk> deficiency, as well as our anti <unk> antibody for us <unk> and perfect.

The Gtx 102 study for Angelman syndrome is progressing well and we remain confident in the program.

The results we shared in 2020 from the original five patients led us to re imagine what is possible for patients with Angelman syndrome gives.

Given the importance of this program we've looked at ways various ways to accelerate this program and.

And recently, we amended our agreement with genetics to allow us an additional option to acquire them at an earlier time point based on the interim data.

I'll, let camille share more in her section about the favorable safety profile and enrollment status across the regions. We also look forward to providing more robust interim update in mid 2022.

On the commercial side the teams continued developing and executing their plans to define more patients who could benefit from Chris Vita those OEM <unk>. These.

These efforts are supported by the work our clinical and regulatory teams are doing with country specific authorities to enable greater access to these therapies.

We will leverage our global commercial medical affairs regulatory function to bring his chiesa.

Novel High potent an approved antibody to patients where the current standard of care does not adequately reduce the LDL cholesterol in patients with HMH.

Since closing the deal we transferred the marketing authorization in Europe and have begun the process to submit reimbursement dossiers.

While this review process of negotiations can take time, we will leverage the team that currently supports <unk> to respond to requests for named patient access within Europe .

Feedback from the Kols community has been enthusiastic for the important role of Keith could play in the management of familial hypercholesterolemia.

Keith It gives us a fourth product across five different indications that will generate regenerating revenue for the company. This creates a diversified base of value that will help support our continued clinical execution for years to come.

I will let the team go into more detail on their progress in the quarter, Eric can you begin.

Yeah, well.

But you should see in the second half of the year that the revenues continue to accelerate.

The, let me, Erik, do you want to talk through this, the quarter-on-quarter thing?

So yeah, we feel good about the guidance range of 250 to 260.

Thank you Emil and good afternoon, everyone.

I think it's kind of reiterating what we just went through.

Commercialization teams have continued to adapt and evolve our strategies to meet the constantly changing landscape for Christina.

So we're reconfirming that today.

Within the North American territory with strong underlying demand from adult and pediatric patients with <unk> and Tio continues.

Appliance among patients who are already on therapy remains high with patients reflecting on how much better they feel once they start receiving Chris feeder.

In the first quarter approximately 80, new patients began therapy, which is consistent with the steady growth we have seen over the last few quarters.

These increases are largely driven by the community prescribers were nearly 50, new doctors wrote a prescription in the first quarter.

Yep, so seasonal pattern plus improvement in Latin America.

We feel good about what Christie is continuing to grow and I think the demand is strong and the, Appliance and persistence has been excellent, so people, once they get on, they really do stay on the sprout, probably as good as any we've ever seen.

In Latin America, we're continuing to see accelerating demand for Chris Vita driven by patient seeking therapy, we've been named patient programs.

All right.

So we're, we think it's a great product will continue to grow.

Okay.

Next question.

This is particularly the case in Brazil, the largest market in the region.

Oh, can I ask another one?

Where we are in the final stages of full reimbursement negotiations with the authorities.

Thank you.

Ordering in this region can be variable from quarter to quarter, but it is clear there is a strong demand for Christina when the patient and medical communities.

Yeah, consistent with what Marty would just stated was, we, we, the first quarter was pretty much in line with our expectations. We had anticipated some seasonality issues as a result of the re-optimization process. In addition, you know, the Omicron virus impacted us a bit more than it had, than COVID had impacted us previously, as we had about three quarters of our sales force out on protocol at some point in the first two months of the year. So there was some impact there.

For <unk> revenue in the first quarter 2022 grew 29% compared to the first quarter of 2021.

Consistent with previous years, we're expecting steady growth throughout the year with quarterly splits.

As is typical there was some seasonality patients work through the reauthorization process with their insurance providers at the beginning of the year.

As we saw in 2021.

We expect stronger revenues in the second half of the year and we maintain that 2022 casino revenue and ultra Genex territories will be between $250 million to $260 million, representing 40% growth in their products fifth year.

Um, just, oh.

Turning now to the jewelry is.

Go ahead.

As a reminder, we will no longer provide detailed start form and other metrics for this program.

Okay.

Thank you.

We are past the early quarters of launch.

And with regards to the rest of the world, you know, I stated the increasing momentum in Latin America as more and more patients are being granted injunctions and receiving reimbursed therapy. And that's going to continue to accelerate as we get full reimbursement in Brazil and across other countries in Latin America.

You're on.

In the U S. The number of new start forms and patients on reimbursed therapy are consistent with the steady growth we saw in recent quarters.

Okay.

While we are seeing utilization that nearly all of the major centers for inborn errors of metabolism, we have begun to find new prescribers at some of the neuromuscular centers of excellence we.

We will increase our efforts on these specialists as we look to expand the network of prescribers.

Outside of the U S use of the <unk> continues to remain patient and early access programs in Europe .

And then with regards to Europe, we've seen steady growth, and name patient sales with the job.

Specially driven by France and Italy, and now we're expanding that across other countries, in Europe, and subsequently, the potential for Meaningful Increasing Revenue in 2023 with with FK's, Good.

In Italy, there continues to be meaningful demand.

Our named patient program.

Hopefully that answers your question, Yigal.

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

We are continuing to work through the process to get full reimbursement approval.

This can take a little bit of time to complete.

For the year, we are reaffirming the guidance range of $55 million to $65 million that we put out in January .

I commend the teams work to generate more than 50% growth in this product's third year post approval.

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

Let's go on to the next question.

And then hopefully this wasn't already asked, but in terms of just the quarter-over-quarter trends for North America, I'm assuming that the 45 million in this most recent quarter was a seasonal effect.

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

Yeah, thank you.

And then if you could just comment on the rest of the world, look, very, very nice increase quarter-over-quarter.

Company revenue for the three months ended March 31, 2022 totaled $79 9 million Christina.

Christy that revenue and ultra Genex territories were $54 6 million, including $45 2 million from the North America profit territory territories, and net product sales of $9 4 million in other regions.

Total royalty revenue for the sales of Christy that in the European territory were $4 8 million.

<unk> revenue for the first quarter of 2022 was $12 4 million net savvy revenue for the same period was $4 9 million. We expect these revenue revenues may modestly increase over time.

Recall in the fourth quarter of 2021, the technology transfer activities were substantially completed and revenue from this agreement going forward will be minimal.

Excluding daiichi revenue in both periods total revenue has grown 35% in the quarter compared to the first quarter of 2021.

Our total operating expenses for the first quarter of 2022, we're at $216 6 million, which includes research and development expenses of $143 2 million SG&A expenses at $67 3 million and cost of sales of $6 1 million.

I said note. This also includes expense related to noncash stock based compensation of $29 4 million.

As we have discussed in prior quarters, we continue to expect expect our R&D spend to somewhat increase in 2022 as we support three pivotal gene therapy clinical studies.

The UX one for three phase III clinical study NOI and Angelman and Angelman phase one two study and the phase one two study for our most advanced mrna program <unk>, III and GSD <unk> and a number of other preclinical activities as we get ready to advance the next programs into the clinic.

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

For the quarter ended March 31, 2022, net loss was $152 3 million or $2 19 per share. The net loss includes $9 $3 million decrease in the fair value of equity investments.

Next caller.

So if you could just comment a little bit on the thinking behind that.

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

Thank you.

Yeah, well.

Thank you Marnie and I too wish everyone. A good afternoon, and my section I will briefly provide status updates for our six clinical stage programs.

Putting the Gtx 102 phase one two study being conducted by our partner genetics before turning the call back to Emil.

Thank you.

The, let me, Erik, do you want to talk through this, the quarter on quarter thing?

Starting with the gene therapy programs.

Next we have Joon Lee with Truist Security.

I think it's kind of reiterating what we just went through.

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

Hi, thanks for taking our questions.

Similarly, <unk> 701 for the treatment of Wilson disease is currently dosing patients in our seamless phase 123 randomized placebo controlled study.

<unk> for the treatment of ornithine <unk> or OTC deficiency is currently in the final stages of study start up and site activation.

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

Okay outside of gene therapy, <unk>, three or <unk>, an anti <unk> antibody has begun dosing patients in the seamless phase three study for pediatric and young adult patients with osteogenesis imperfecta.

We are also planning to initiate an additional study in children less than five years old in the second half of the year.

In the prepared remarks regarding GTX-102, you mentioned enrolling in drug and a comparator group. Can you elaborate on what you mean by the comparator group?

Gtx 102, the Asl in development with our collaborator genetics for patients with Angelman syndrome continues to dose patients under the amended phase one two protocol.

In the UK and Canada, both cohorts four and five have expanded following a review of available safety data by their respective DSM b.

And also, you said you have administered up to five doses in some patients.

We began dosing patients in December with some receiving up to five doses so far as.

Are you able to share that in cohort four, five, or in the U.S.?

As we have previously indicated the initial assessments of these patients have shown early and encouraging signs of clinical activity and multiple domains similar to that which we saw in the original five patients at these low doses.

Thank you.

So, in the U.S. with the FDA agreement that we are going to dose, we dosed four patients with two MIGs once per month, that was the agreement.

To date, there have been no drug related safety issues or lower extremity weakness in the newly treated patients.

They also want us to enroll another four patients. Not randomized, another four patients to be enrolled to simply just do the assessments on them without drug dosing, all right?

In the U F eight patients allocated one to one and that drug and comparator groups have been enrolled.

So that's the four comparators.

We have received some anecdotal reports have limited improvements from these patients being dosed receive drug at the to make dose level.

That was described before, but perhaps it got missed.

To reiterate our most important finding for this stage of the study across all regions. There have been no reports of lower extremity weakness in any of the patients treated under the amended protocol.

We look forward to providing a more robust update on this program in mid 2022.

<unk> three our first mrna treatment modality being developed for 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 repeat dosing phase of the study are anticipated in the second half of this year.

So that's what's happening, XUS.

Yeah, consistent with what Marty would just stated was, we, we, the first quarter was pretty much in line with our expectations. We had anticipated some seasonality issues as a result of the reauthorization process. In addition, you know, the Omicron virus impacted us a bit more than it had, than COVID had impacted us previously, as we had about three quarters of our sales force out on protocol at some point in the first two months of the year. So there was some impact there.

With these updates I will now turn back the call to Amy Thank you.

The question on up to five, we're talking about the patients now, XUS.

But, Consistent with previous years, we're expecting steady growth throughout the year with quarterly splits.

And so the first few patients have actually gotten all four doses plus one maintenance dose.

Thank you Camille before we shift to the Q&A portion of the call I'll provide a quick reminder of the key upcoming milestones for the company.

All right, so that's five doses, all right.

And others have lesser numbers.

Consisting with what you saw in 2021 with increasing sales in the second half of the year.

We haven't put out the specifics of the time course of all of it, but the point would be that we have now multiple patients who've gotten five doses of drugs, without any lower extremity weakness.

And with regards to the rest of the world, you know, I stated the increasing momentum in Latin America as more and more patients are being granted injunctions and receiving reimbursed therapy, and that's going to continue to accelerate as we get full reimbursement in Brazil and across other countries in Latin America.

So just to clarify the issue that simply exposing the patient to the drug repeatedly is not gonna cause the problem by itself at any dose level that we're at.

And then with regards to Europe, we've seen steady growth, and named patient cells with the jovial.

Specially driven by France and Italy, and now we're expanding that across other countries, in Europe, and subsequently, the potential for, Meaningful Increasing Revenue in 2023 with FKG.

Just to clarify, you know, what's the rationale for having a comparator that is not a placebo?

Good.

Seems to be confidence program and look for opportunities to accelerate development.

Unknown Speaker Well, I think they want to know what's going on.

Hopefully that answers your question, Yigal.

<unk> hundred 40, <unk> Genesis Imperfecta will continue enrolling patients in the phase II portion of the study and expect to provide an update on the dose strategy. We have selected for the phase III portion in the second half of the year separately, we expect to initiate.

Well, you want me to read the FDA's mind.

Let's go on to the next question.

The FDA, was looking, knowing that a placebo is hard to do, I think what they're looking for is some measure of how consistent you would do these complex psychologist-driven tests, on a patient and how what that would look like just to understand the variability of the method.

When they're done repeatedly, that's the basis for it.

Yes, thank you.

Thank you.

Next we have Joon Lee with Truist Security.

Hi, thanks for taking our questions.

<unk> in children under five years old in the second half of the year.

In the prepared remarks regarding GTX 102, you mentioned enrolling in drug and a comparator group.

Across the gene therapy pipeline, we will continue enrolling the phase III for <unk> 401 in the phase 123 for <unk> 701, we also expect to finalize study.

Can you elaborate on what you mean by the comparator group?

Steady startup activities for <unk> 301, and begin dosing patients in mid 2022.

On the manufacturing side, we will continue to build out our facility in Bedford, Massachusetts was on track to begin producing material next year.

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

All of these programs create a distinct opportunity to make a meaningful difference for patients with a rare genetic disease.

We look forward to sharing further updates with you throughout the year. You also may have seen that we have launched our inaugural ESG report for 2021 last month.

Part of the meaningful evolution to the journey, we've been on for the last 12 years of the company. We will continue to build on this foundation to report on our progress.

It's not a true control.

And also, you said you have administered up to five doses in some patients.

With that let's move onto your questions.

I think they just wanted to look at how much variation would you see?

Are you able to share that in cohort four, five or in the US?

Operator, please provide the Q&A instructions.

just in measuring patients with the people doing it.

Thanks.

Thank you as a reminder to ask a question you will need to press star one on your telephone to withdraw your question press the pound key.

So it's a test of the system, really, and not really a control group in that sense, and it's fine.

I think what we're confident in is patients don't really change much. But there's no doubt when you do measures like this, there's going to be some variation.

The question is whether what we see in our patients is beyond variation, and we've addressed that before to say that the imaginative change seen, for example, in the Vineland score that was presented last year at FAST, showed that the level of change observed was far beyond what you would see in placebo change over time or control group for natural history.

Ask that you limit your questions to one question and one follow up please standby, while we compile the Q&A roster.

So we're comfortable, but that's what that four patients are for, and we're complying with the FDA's request on just having four more patients getting assessed.

Thank you.

Our first question comes from Gena Wang with Barclays.

Thank you.

Thank you for taking my questions I have two questions Julien program. So maybe can you comment on any chemistry differences between locking equally assay.

Okay, let's move on.

So, so in the U.S. with the FDA agreement that we are going to dose, we dosed four patients with two MIGs once per month, that was the agreement.

They also want us to enroll another four patients. Not randomized, another four patients to be enrolled to simply just do the assessments on them without drug dosing, all right?

Roche is Lockheed asset and then my second question is based on the comments you made that early upbeat for the Gtx 102.

Should we expect some good cost clinical benefit at the midyear update beyond the two CGI score improvement in two domains to support the right dose.

Thank you.

Thank you gena so on the chemistry differences I am I am.

Deep fulfillment with the specifics of the Roche molecule and all the different linkages because there are a lot of linkages. We know that it has locked in clegg acid GAAP model like ours is there are some specific differences on the sequence no doubt and some other minor chemistry changes, but I think the biggest changes where differences between worthy.

The next question comes from Joseph Schwartz with SBB Security.

Hi, I'm Doreen Dialing in for Joe.

<unk> and the overall safety profile of a product.

Not just the chemistry, it's also the dose and the potency that will determine it and we believe based where ours is targeted at is very potent and that the dose range will be at the lower end of the range.

Which is partly in part related to the potency of the locked it click asset type of ASO. So we're confident about the chemistry have and while they are both to have LMA block nucleic acid components I can't say it those differences are that you can make any conclusions from those differences alone.

Thank you for taking our questions.

So that's the four comparators.

Now with regard to the opt in.

You've previously mentioned using a multi-domain responder index as a possible endpoint for VTX-102.

That was described before, but perhaps it got missed.

The opt in just gives us an opportunity to execute earlier on interim data and it just gives an opportunity to potentially accelerate the program.

So that's what's happening, XUS.

The decision on efficacy is not doesn't indicate.

That we would need more or better or worse efficacy is just option for us based on the interim data to execute the acquisition earlier.

Under a different somewhat different set of terms, but we think it is.

As a potential way for us to accelerate the program depending on what we see in announced mid year.

Thank you.

So curious what the receptivity is to that endpoint from the regulatory agencies in Phase 3.

The question on up to five, we're talking about the patients now, XUS.

Thank you. Our next question comes from Eagle Djokovic with Citigroup.

Okay.

Memorial Sloan Kettering.

Yes.

Stephanie.

We do.

Operator.

This might not be related to our call.

Okay.

Well move onto your questions.

And then secondly, are there other domains you would consider for the MDRI besides the five in the CGI-IAS?

<unk> Ahmad with Bank of America.

And do you know what the minimally important differences are for the individual domains to set as a threshold to be considered a responder?

Hi, Thanks for taking my questions.

Thank you.

And so the first few patients have actually gotten all four doses plus one maintenance dose. All right, so that's five doses.

I just wanted to get a sense from you on how you plan on aligning.

Protocol going forward between FDA and EU regulators, assuming that youre going to look into your pivotal study for Angelman.

And then secondly can you talk about the cadence of growth for Christie, thus far it's starting to move into sort of the mid stage of growth.

What was the main growth driver this quarter and where do you see the remaining remedy for growth on a go forward basis. Thank you.

Wow, this is a deep dive into clinical study design.

All right.

And others have less lesser numbers.

Good.

We haven't put out the specifics of all of the time course of all of it. But the point would be that we have now multiple patients who have gotten five doses of drugs, without any lower extremity weakness.

I'll deal with the protocol piece first and Eric maybe you can talk about the areas of growth for Chris feed after I finish with the first part.

So just to clarify the issue that simply exposing the patient to the drug repeatedly is not gonna cause the problem by itself at any dose level that we're at.

So on aligning protocols, it's not actually that difficult both protocols are treating.

Essentially a once a month, but it's just a different dose and regimen for administration, so our expectation to align them as in will align them in the phase II, we will take our data from ex U S from Canada, and the UK that show us that the drug is safe and that the new administration strategy.

As appropriate and.

And bring that data along with the other safety data we have to the U S.

And request that they opened essentially an amendment that will align all three regions under the same protocol. We think we have enough data at this point to be able to show that the new regimen in the doses are are safe and while we havent dosing patients at two Mig it would give us an opportunity then to.

Two.

Bring the higher dosing in that we're using ex U S.

<unk>.

Other part we would align for individuals who happen to be at lower doses, whether in the U S or outside of the U S.

Dose was determined that need to be higher we will we will provide a makeup dose to those patients that will help bring their load level up in line with the other patients who will get them.

They need to be so we will take the data to them and get the U S. Open we believe with that ex U S data and get everyone aligned in phase III from there going forward in phase III, then we'd have the world or.

All regions aligned on a single phase III program.

Very good.

Just to clarify, what's the rationale for having a comparator that is not a placebo?

I don't understand, we can't, I mean, we've got to.

So let's talk about the crispy the cadence of growth is.

Thank you.

Well, I think they want to know.

Well, you want me to read the FDA's mind, the FDA, was looking, knowing that a placebo is hard to do, I think what they're looking for is some measure of how consistent you would do these complex psychologist-driven tests, on a patient and how what that would look like just to understand the variability of the method.

When they're done repeatedly, that's the basis for it.

For those of you who don't know what the Multidomain Respondrix is, it's a technique for just analyzing endpoints that allows you to capture the totality of the data across multiple domains.

It's not a true control.

It's been moving toward adults with Eric maybe you can provide a little more color on the growth and Christy that overtime.

I think they just wanted to look at how much variation would you see?

I've written a paper on it with our head of biometrics, PK Tendon, and we've also had meetings with the FDA, including a large number of senior FDA people, about the meaning of the approach.

So it's a test of the system, really, and not really a control group in that sense, and it's fine.

just in measuring patients with the people doing it.

They are interested in it.

I think what we're confident in is patients don't really change much. But there's no doubt when you do measures like this, there's going to be some variation.

They have questions still, but it needs kind of a test case, and perhaps Angelman is the test case.

So as far as procedures concern, we're expecting to steady growth in North America as we've seen.

It's not been accepted yet, although it was.

So we're comfortable, but that's what that four patients are for, and we're complying with the FDA's request on just having four more patients getting assessed.

In the sense that we ran an MDRI in our MEP-SEVI program that was approved, it did, in my mind, hit the end point in the small study showing the power of the MDRI to capture advocacy.

If we were to approach an endangerment syndrome, the five domains we're talking about are probably the ones we would pick.

The seizure domain, because they're on seizure meds and they've all been in control, there's not much power there.

If they're having a lot of seizures, it could be also a domain.

But I think the other domains we would use are basically the communication domain, receptive and expressive, as well as sleep, behavior, basically through the Vineland and we would also look at, Fine Motor and Gross Motor Scales.

<unk>.

We've been building momentum in Latin America for the last couple of quarters.

Expect that to continue to accelerate.

<unk> growth although it.

As we stated.

Growth.

For each of those scales, like the Baileys for express communication and the Fine Motor, those tools have normative data as well as what are considered MIDs, data to support them.

Not necessarily in the Angelman Center, but in general.

It was recognized in <unk>.

And so we think there's a lot of those types.

Stages, it was kind of lumpy in how it grows from quarter to quarter, but overall on an annual basis, it should be steady accelerating growth.

Thresholds that we could capture.

I have a, we have an entire team, headed by Ali Steiner, who is terrific at this stuff, and they can generate more MIDs or supportive data, but we feel like it's a very powerful way to look at heterogeneous complex diseases like Angeman.

That said, if we had to, we could do CGI.

So at this point, I feel like the good part is we're talking about magnitude of changes that are meaningful, easily captured, therefore you can do it practically any way you want to, and that'll work.

We see tremendous power in the CGI, and the FDA has accepted it before, so I don't see any risk here.

We do one or the other.

We can always put the MRI as a secondary and gain the benefit of it there if we get approved off of a primary CGI Angeman syndrome.

And then when you look at Europe .

Yes.

We're seeing increase we're seeing steady sales growth and.

Named patient sales for <unk>.

Joe.

Some expansion across Europe for named patient sales with Adobe.

We expect some meaningful start to recognize meaningful growth.

<unk> revenue in 2023 and beyond.

Okay, great.

Thank you.

Thanks, Eric I think in.

In the U S. I think one of the elements of color that.

We can provide here is that there is a continuing shift to more adult patients and pediatric patients.

And that.

Nearly half the scripts or a prescription of the new star forms are are coming from new prescribers with new paint new adult patients. So.

There is a very broad diverse group of doctors out there who are treating patients and thats by.

By seeking and finding those patients will continue to find patients when we find them. We have a very high rate of conversion to people, who actually want to prescribe. So it's about getting the word out and so thats.

Continuing to be a driver of steady growth is finding those new doctors new patients in the U S and we will continue driving that activity.

That's good for you Tim.

Thanks Raimo.

Thank you very much.

Thank you.

Thank you. Our next question comes from Yaron Werber with Cowen.

Thank you.

Okay, let's move on.

Hi, This is Brendan on for you around thanks for taking my questions guys. Just a couple quick ones from us.

Our next question comes from Maury Raycroft with Jefferies.

Thank you.

First I wanted to ask actually about the OTC pivotal study.

I just wanted to see what you can tell us maybe about enrollment and recruitment there I know originally.

Hi, thanks for taking my question.

The next question comes from Joseph Schwartz with SBB Security.

Thinking to get underway earlier this year now it looks like it's going to be closer to starting screening mid year. So just wanted to see if there's any color you can provide.

Hi, I'm Drewie Dialing in for Joe.

I was going to ask a question about Angelman safety.

And then on an angelman, assuming a mid year update really focuses on the ex U S study.

So based on the time course of the SAE and your original patient number two disclosed previously, it appears to be a peak dose effect.

The U S kind of get going here.

But how do you get comfortable with cumulative dosing effects since the SAE occurred about six to 30 days after the last dose across the five patients?

Well, the reason we get comfort that it's not a cumulative is because the actual dose, cumulative dose at which someone has a problem with highly variable between patients and unrelated in severity.

Do you have a sense of maybe the timing over the next six to 12 months of your planned cadence for additional states from potentially higher doses.

The fifth patient had one dose, only 20, and had the effect.

We had also the first patient that had 106 milligrams, and had mild, mild problems.

So, There's not much relationship to the accumulation and the time course of the effect, like the six days or so.

The time course of the adverse effect doesn't fit the efficacy effect, so this has nothing to do with the drug acting as an ASO in the brain tissue, it has to do with an effect that's very local, like something irritating the nerves there, right, so it is really something operating on a different time course, different mechanism, and everything we have says it's, A Concentration Dependent Effect, And what we're seeing right now, dosing for as many months as we have, is we're not seeing the effect of accumulation causing the problem, right, Maury, so that was your question, we've dosed, why we told you we dose now multiple patients have given five doses over a month, right, and not seen the effect, so if accumulation would have done it, then they would have had a problem, but they haven't, so I think it verifies our view that this is an acute toxic kind of effect due to high concentrations, it's more like an irritation of the meninges and the nerve roots.

And we think that the change administration method, dosing administration method, are going to mitigate that, and we think we've seen that that's true.

Good so the OTC program among the three gene therapy programs, we had set the <unk> 401 for <unk> is kind of our priority. There are a lot of patient ready we were able to get through the process a little faster and are driving that one ahead, which is now enrolling we purposely then put the OTC program.

Got it.

A little further behind remember, we're running four pivotal programs at once which is a lot for any company. So the OTC is.

Okay, that's really helpful.

By design.

Behind it has not started enrolling but the sites are getting started and.

We've gotten through the process and regular regulatory process. So I think we're aligned up to go ahead and.

Thanks for answering my question.

We will start enrolling and I think we'll do fine.

Thank you.

<unk> hundred one clearly we will I think be the first gene therapy to get through the phase III processing yield data.

Our next question comes from Salveen Richter with Goldman Sachs.

Thank you for taking our questions.

Now with regard to Angelman.

Hi, this is Tommy on for Salveen.

You've previously mentioned using a multi-domain responder index as a possible endpoint for GTX-102.

Right now we are coming out mid year with the current dose regimen, what we said in the past is that we would expect to take what we've learned and what doses, we've cleared and initiate new cohort starting at those new doses. So we can load patients.

Thanks for taking our question.

At the higher doses that have been cleared as safe.

And we would expect to be doing that this year. If we then are able to show that that dose is safe and reaches.

So curious what the receptivity is to that endpoint from the regulatory agencies in Phase 3.

So the phase III would be expect to be something we would we start next year.

That gives you a little more color on the timeline.

And then secondly, are there other domains you would consider for the MDRI besides the five in the CGI-IAS?

Yeah, that's great thanks very much.

And do you know what the minimally important differences are for the individual domains to set as a threshold to be considered a responder?

Thank you. Our next question comes from <unk> <unk> with J P. Morgan.

I wanted to follow up about Angelman safety.

Thank you.

Hi, This is Tiffany on for Corey.

So at this stage.

I guess, how many patients you can expect initial safety and efficacy data from that.

There will be an update and what would be the cutoff share inclusion there would it be simply any data ahead of a specified date before that readout are kind of a required follow up is there anything at this time.

Wow, this is a deep dive into clinical study design.

Well, we would expect since we said that all eight patients in U S were enrolled.

Very good.

And for patients dosed at the two Meg dose level.

Thank you.

We would expect to provide all the data we have on them at that point in time.

For those of you who don't know what the Multidomain Responder X is, it's a technique for just analyzing endpoints that allows you to capture the totality of the data across multiple domains.

<unk> is just an interim look so we'll provide as much as we can on four patients that we will have received multiple doses of <unk> as well as then the patients ex U S. In cohorts four and five I would've gotten the higher doses and been going through the titration.

Got it.

Like 16 patients.

Okay.

Yes.

We've enrolled GOR and five and the four yes.

Okay great.

Basically, your confidence by the SEs were dose specific rather than molecule specific, specifically as it relates to like the chemistry and the binding site of your ASO.

I've written a paper on it with our head of biometrics, P.K.

Tendon, and we've also had meetings with the FDA, including a large number of senior FDA people, about the meaning of the approach.

Thank you. Our next question comes from Yigal <unk> from Citigroup.

And then an update maybe of where you're at now with dose escalation, what level you think could be reached by the by the update?

They are interested in it.

Hi team. Thank you very very much for taking the questions apologies for earlier I was juggling multiple calls.

Thank you.

Sure, so thank you for your question.

They have questions still, but it needs kind of a test case, and perhaps Angelman is the test case.

I think you're asking whether the safety effect was related to the molecule versus the chemistry.

Just a question on the guidance for Chris Vita in the Ultrasonics territories, so as far as I understand you did $55 5 million and <unk> 21, 54, 6% and.

I think from the safety work done on the molecule, meaning the sequence itself.

It's not been accepted yet, although it was.

MEP-CEB in the sense that we ran an MDRI in our MEP-CEB-E program that was approved, it did in my mind hit the end point in a small study showing the power of the MDRI to capture efficacy, If we were to approach an endangerment syndrome, the five domains we're talking about are probably the ones we would pick.

The seizure domain, because they're on seizure meds and they've all been in control, there's not much power there.

If they're having a lot of seizures, it could be also a domain.

And the most recent quarter.

For each of those scales, like the Bayley's for express communication and the fine motor motor, those tools have normative data, as well as what are considered MIDs, data to support them.

So just if you could just help elaborate a little bit on the on the <unk>.

Rationale behind the $2 50 to $2 60, just because based on the last two quarters.

Does seem perhaps a touch aggressive thank you.

Not necessarily in the Angelman Center, but in general.

We're comfortable that it's not hitting off-site target effects in other situations.

And so we think there's a lot of those types.

When you look at the pattern of the safety effect, the fact that it peaks in a week or two and then declining over several weeks, it doesn't fit the specific antisense-ongamilutide pattern of its concentration and presence.

Well, we have some experience now we're a bit of time on the program. So we're we're actually comfortable with how it performs and how the second half of the year stronger and maybe Eric do you want to touch on that our Marni.

It fits a different kind of thing.

Thresholds that we could capture.

What we do know, and it's been published, that ASOs in general have a nonspecific chemistry toxicity kind of thing that can be demonstrated in vitro.

We do one or the other.

Eric.

If you put a lot of it in there, it goes in, will bind certain proteins, and cause some toxicities. And so this tells you, you just have to manage the local concentration carefully at the time you administer it.

That said, if we had to, we could do CGI.

We can always put the MRI as a secondary and gain the benefit of it there if we get approved off of a primary CGI Angeman syndrome.

Yes so.

That chemistry effect can be enhanced by being a lacto-nucleic acid.

We see tremendous power in the CGI, and the FDA has accepted it before, so I don't see any risk here.

But the lacto-nucleic acid also gives you longer half-life and greater potency.

With regards to the steady growth in <unk>.

So the question is, how do you balance those benefits of lactic acid versus the toxicity issues?

In North America, we're seeing accelerating growth in Latam.

And expecting.

Potential for reimbursement by the end of end of the year, which will help speed up the trend.

Transition patients that have been waiting for.

Treatment.

The injunction process of named patient sales process.

So Latin America will contribute did you want to add I was just going to add you got if you look at the quarterly progression in 'twenty one.

I think there are ways to look at that.

Thanks, and just to follow up on the dose escalation, the progress there.

And we think with the molecule we have and where it's targeting and the fact that, Only a milligram in a monkey can provide sufficient knockdown, which is well below what's been seen with other ASOs.

Thanks.

Okay, great.

We think we have the glove of potency that the benefit of LNA can be obtained without risking the toxicity issues that happen from those more stable and those type of ASOs.

Thank you very much.

In terms of how the sales progress throughout the year, we expect the same in 2022 as well so youre going to see.

Thank you.

Our next question comes from Maury Raycroft with Jeffries.

First quarter is always has seasonality impact in the prion work et cetera, and then there's just some timing between Q4 and Q1, but you should see in the second half of the year that revenues can continue to accelerate.

Hi, thanks for taking my question.

I was going to ask a question about Angelman safety.

So, based on the time course of the SAE in your original patient number two disclosed previously, it appears to be a peak dose effect, but how do you get comfortable with cumulative dosing effects since the SAE occurred about 6 to 30 days after the last dose across the five patients?

Yes, we feel we feel good about the guidance range of $2 50 to two tech space that we're reconfirming that today.

Thank you Rob pattern seasonal pattern plus improvement in Latin America, we feel good about Chris we are continuing to grow in.

The demand is strong in the.

And to persistence has been excellent so people once they get on they really do see on the right.

Probably as good as <unk> ever seen so we're we think it's a great product will continue to grow.

Alright, Okay question.

Sure.

Oh can I ask another one.

Sure.

Oh.

Go ahead Tom.

Okay.

And then hopefully this wasn't already asked but in terms of just the quarter over quarter trends for North America, and assuming that the $45 million.

This most recent quarter was seasonal effects.

And then if you could just comment on rest of world look very very nice increase quarter over quarter. So if you could just comment a little bit.

On the.

Thinking behind that.

Okay.

Yeah well.

Let me be Eric do you want to talk through.

The quarter on quarter thing I think it's kind of re aggregating when we just went through.

Consistent with Marty will just state it was weak the first quarter was pretty much in line with our expectations.

We had anticipated some seasonality issues David.

As a result of the re optimization process.

In addition.

The only common virus impacted us a bit more than it had.

Then COVID-19 impacted as previously is we had about three quarters of our sales force out on protocol at some point in the first two months of the year.

So there was some impact there.

Yes.

System with previous years, we are expecting steady growth throughout the year with quarterly splits.

Consistent with what you saw in 2021 with.

<unk> sales in the second half of the year.

And with regards to the rest of the world.

That stated increasing momentum in Latin America is more and more patients are being.

Being granted injunctions and receiving reimbursed therapy.

And thats going to continue to accelerate as we get.

Full reimbursement.

In Brazil and across other countries in Latin America.

Then with regards to Europe .

But we've seen steady growth.

And named patient sales with the jewelry.

Particularly driven by France, and Italy, and now we're expanding that across other countries.

And in Europe .

And subsequently.

The potential for.

Meaningful increasing revenue in 2023 with that CAGR.

Good.

Answer to your question well, let's go onto the next question.

Thanks for color.

Thank you.

Thank you and next we have joon Lee with <unk> Securities.

Well, as we've said, several patients have gone through five doses, which means they've gone through the four doses and have gone into maintenance.

Hi, Thanks for taking our question.

In the prepared remarks regarding gtx, one on one or two you mentioned enrolling in drug and a comparator group can you elaborate on what you mean by the comparator group and also you said you have administered up to five doses. Some patients are you able to share that same cohort four.

Or in the U S. Thank you.

We haven't really disclosed all the levels of dose titration.

Yes, so so in the U S with the FDA agreement that we're going to dose we dosed four patients with two migs once per month that was the agreement.

There has been titration, and we'll put out all that detail on titration and what dose level and outcomes in all the patients at the midyear.

It's not really appropriate to start putting that out yet.

They also want us to enroll another four patients.

Not randomized and another for patients to be enrolled is simply just do the assessments on them without drove drug dosing alright.

So that's the four comparator that was described before but perhaps.

Got missed so that's what's happening ex U S. The question on up to five we're talking about the patients now ex U S.

As I said, multiple patients have reached five, which means they had four loading doses and then one dose of their maintenance regimen, which happened three months after the fourth dose.

Thank you.

And so the first few patients have actually gotten all four doses plus one maintenance dose.

Alright, so thats five doses and others have less lesser numbers, we haven't put out the specifics of all of the time course of all of it but.

The point would be that we have now multiple patients who've gotten.

Five doses of drug.

Without any lower extremity weakness so just to clarify the issue that simply exposing the patient of the drug repeatedly is not going to cause the problem by itself at any dose level.

Well, the reason we get comfort that it's not a cumulative is because the actual dose, cumulative dose at which someone had the problem was highly variable between patients and unrelated in severity.

Just to clarify whats the rationale for having a comparator that is not a placebo.

I don't understand.

Well I think they wanted to.

Well you want me to read the Fda's mind the FDA.

Does looking knowing that a placebo is hard to do I think what they are looking for is some measure of how consistent you would do that you would do these complex psychologist driven tests on a patient and how what that would look like just to understand the variability of the methods when theyre done repeatedly.

That's the basis for it it's not a true control I think they just wanted to look at how much variation would you see.

Just in measuring patients with the people doing it so.

So it's a test of the system really is not really a control group in that sense and it's fine I think what we're confident is the patients don't really change much.

But there's no doubt when you do measures like this there's going to be some variation.

<unk> is whether what we see in our patients is beyond variation and we've addressed that before to say that the magnitude of change seen for example in the Vineland score that was presented last year at fast showed the level of change observed was far beyond what you would see in placebo change overtime or control group for natural history.

So we're comfortable with what that four patients or four and we are complying with the Fda's request on just having for more patients getting assessed.

Thank you. Thank you okay.

Our next question comes from Dajan Ha, Westifel.

Let's move on.

Thank you. The next question comes from Joseph Joseph Schwartz with SBB Securities.

Dagon, are you there?

Hi, Andrew dialing in for Joe. Thank you for taking our questions.

Operator, why don't we move to the next question?

You previously mentioned using a multi domain responder index as a possible endpoint for Gtx one two so curious what the receptivity is sure that endpoints from the regular regulatory agencies in phase III and then secondly are there other domains you would consider for that and besides the five and the CGI.

Okay, our next question comes from Jeff Hung with Morgan Stanley.

And do you know what the minimally important differences are for the individual domain.

Cash flow can be considered a responder. Thank you.

Well this is a deep dive into the clinical study design very good. Thank you.

Thanks for taking my question.

For those of you don't know what the multi domain responder rates as it's a technique for just analyzing endpoint that allows you to capture the totality of the data across multiple domains.

I've read a paper on it with our head of Biometrics PK tendon and we've also had meetings with the FDA, including a large number of senior FDA people about the meaning of the approach. They are interested in it they have questions still but it needs a kind of a test case and perhaps angelman is the test case is.

Been accepted yet although it was except in the sense that we ran in <unk> in our <unk> program that was approved it did hit the endpoint and the small study showing the power of the MRI to capture efficacy.

If we were to approach it in Angelman syndrome, we would the five domains were talking about are probably the ones. We would pick the seizure domain because they are on seizure meds and they've all been in control that much power there if they ever having a lot of seizure that could be also a domain, but I think the other domain, we would use our basically the communication does.

Main receptive and expressive as well as sleep behavior, which basically through the Vineland and we would also look at.

Fine motor and growth motor scale for each of those scales like the bally's for express at communication and I'm Fine motor motor those tools have normative data as well as what are considered.

Data to support them not necessarily in Angelman syndrome, but in general and so we think theres a lot of those types.

Thresholds that we could capture I have we have an entire team head by Alexandra was terrific at this stuff and they can generate more mid's or supportive data, but we feel like it's a very powerful way to look at heterogeneous complex diseases like age when that said, if we had to we could do CGI we.

See tremendous power in the CGI and the FDA has accepted before so I don't see any risk here with you one or the other we can always put them to rise of secondary gain the benefit of it there if we get approved off of a primary CGI Angelman syndrome. So at this point I feel like the good part is we're talking about magnitude of changes there are.

Meaningful easily capture therefore, you can do it practically anyway, you want too and that will work.

Okay, great. Thank you very much.

Thank you. Our next question comes from Maury Raycroft with Jefferies.

Hi, Thanks for taking my question.

I was going to ask a question about Angelman safety. So based on the time course of the SAE near original patient number two disclosed previously it appears to be a peak dose it back, but how do you get comfortable with cumulative dosing effects since the assay occurred about $6 to 30 days after the last dose across the five patients.

Well the reason, we get comfort that it's not accumulative because the actual dose cumulative dose that was someone had the problem with highly variable between patients and unrelated and severity.

The fifth patient had one dose, only 20, and had the effect.

One patient the fifth patient at one dose only 20 and had the effect. We had also the first patient that had.

We had also the first patient that had 106 milligrams, and had mild, mild problems, so.

106 milligrams.

And had mild mild problem so.

There's not much relationship to the accumulation and the time course of the effect, like the six days or so.

Theres not much relationship to the accumulation and the time course of the effect the six days or so.

The time course of these adverse effects doesn't fit the efficacy effect. So this has nothing to do with the drug acting as an ASO in the brain tissue has to do with an effect that's very local like a something irritating.

Irritating the dinner.

The nerves there right. So it is really something operating at a different time quarters different mechanism and everything we have says.

A concentration dependent effect.

And what we're seeing right now dosing for as many months as we have and we're not seeing the effect of accumulation, causing the problem right. So that was your question was why.

So that was your question, we've dosed, why we told you we dose now for multiple patients, have given five doses over a month, right, and not seen the effect.

So if accumulation would have done it, then they would have had a problem, but they haven't.

So I think it verifies our view that this is an acute toxic kind of effect due to high concentrations.

It verifies our view that this is an acute toxic kind of effect of due to high concentration, it's more like an irritation of Dominion Gs and little nerve roots and.

It's more like an irritation of the meninges and the nerve roots.

And we think that the change administration method, dosing administration method, are going to mitigate that, and we think we've seen that that's true.

And we think that the changed administration method dosing administration method.

Going to mitigate that and we think we've seen that that's true.

Got it.

Got it Okay. That's really helpful. Thanks for taking my question.

Okay, that's really helpful.

Sure.

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

Thanks for taking my question.

Hi, This is Tommy on for Celgene, Thanks for taking our question.

Wanted to follow up about Angel and safety.

Please limit your confidence on why the ethane.

No specific rather than molecule specific specifically as it relates to the chemistry and the binding site.

So and then.

An update maybe on where youre at now is dose escalation what level you think could be reached by the by the update thank you.

Thank you.

Sure. So thanks for your question I think youre, asking whether the safety effect was related to the molecule versus the chemistry.

Our next question comes from Salveen Richter with Goldman Sachs.

I think from the safety work done on the molecule, meaning the sequence itself.

We're comfortable that it is not hitting.

<unk> target effects in other situations. When you look at the pattern of the safety effect. The fact that peaks in a week or two and then the client or several weeks it doesn't fit the specific anti sense oligonucleotide pattern of its concentration and presence at <unk>.

It's a different kind of thing what we do now and it's been published that ASO is in general have nonspecific chemistry toxicity kind of thing that can be demonstrated in vitro. If you put a lot of it in there. It goes in will bind certain proteins in cars.

Some toxicities in so this tells you just have to manage the local concentration carefully at the time you administered that chemistry that can be enhanced by being a lock nucleic acid, but then locked it take us. It also gives you longer half life and greater potency.

So the question is how do you balance those benefits of life to click asset versus the toxicity issues. I think there are ways to look at that and we think with the molecule. We have we're targeting and the fact that one.

One milligram in a monkey can provide sufficient knockdown, which is well below what's been seen with ourselves. We think we have the level of potency that the benefit of Allen they can be obtained without.

Risking the toxicity issue that happened from those more stable and those type of Aso's.

Hi, this is Tommy on for Salveen.

Thanks, and then just a follow up on the dose escalation.

Yes, Sir.

Thanks for taking our question.

Okay.

I wanted to follow up about Angelman safety, basically your confidence on why the SEs were dose specific rather than molecule specific, specifically as it relates to like the chemistry and the binding site of your ASO.

Well as we've said we have a <unk>.

And we will put out all of that detail on titration of what dose level and outcomes and all the patients at the mid year, it's not really appropriate to start putting that out yet but.

As Ive said multiple patients have reached five which means they had for loading doses and then one dose.

Their maintenance regimen, which have three months after the fourth dose.

Thank you.

Thank you. Our next question comes from David <unk> with Stifel.

Dave are you there.

Operator, why don't we move to the next question.

Okay. Our next question comes from Jeff Hung with Morgan Stanley .

Can you talk about what we should expect to see from the Citrusmab and the UXO53 updates later this year?

And then an update maybe of where you're at now with dose escalation, what level you think could be reached by the by the update?

Thanks for taking my question can you talk about what we should expect to see from the <unk> and the <unk> III updates later this year.

Sure.

Thank you.

Okay.

Sure so in <unk>.

Sure, so thank you for your question.

We expect to have.

So in citruzumab, we expect to have, Almost 40 patients enrolled that have gotten two months of dosing and what we'll have is information on their biomarker, the P1B biomarker, which were based on the historical data from the asteroid study in 90 patients, showed a nice correlation between their bone marrow density improvements, and the P1MP.

I think you're asking whether the safety effect was related to the molecule versus the chemistry.

I think from the safety work done on the molecule, meaning the sequence itself, We're comfortable that it's not hitting off-site target effects in other situations.

Almost 40 patients enrolled little have gotten two months of dosing and what we'll have is information on their biomarker. The <unk> borrowing biomarker, which were based on the historical data from the asteroid steady 90 patients showed a nice correlation between their bone marrow density improvements.

When you look at the pattern of the safety effect, the fact that it peaks in a week or two and then declining over several weeks, it doesn't fit the specific antisense oligotide pattern of its concentration and presence.

And that and the <unk> MP. So we'll look at the <unk> marker and other data safety efficacy and to help make a decision we'd put out what our decision is on the dosing algorithms for pediatric and adult patients in the disease. So you'll learn about safety biomarker information at a high level and then.

So we'll look at the P1MP marker and other data, safety and efficacy, and to help make a decision, we put out what our decision is on the dosing algorithms for pediatric and adult patients in the disease.

So you learn about safety, biomarker information at a high level, and then we'll talk about what our dosing strategy going forward and our plan to start phase three.

We'll talk about what our dosing strategy going forward in our plan to start phase III, that's the truth.

That's the Truth-O-Map.

It fits a different kind of thing.

What we do know, and it's been published, that ASOs in general have a nonspecific chemistry toxicity kind of thing that can be demonstrated in vitro.

For O5-3, we're going to have basically single dose, single sending dose data, which we'll look at.

David Caroline H. shampoo Nav wallet, suyaha.com, www.mmm.

305, three we're going to have basically single dose ascending ascending dose data in which we'll look at.

Puerto Rico Right now, we are a dedicated, expert public health team so we are not a private company.

The safety of course, and as well as effects on glucose and other biomarkers and clinical.

Assessments as well.

But because it's early and it's only single dose we wouldn't expect to see dramatic clinical benefit at this point, but we're looking to see clinical activity and the and the Biomarkers endpoints that would help us assess that.

Now let me to say that I didn't mentioned rash on apple, rash on apple, the coverage measures are looming, Beautiful reviews by Brookfield Medical Center, Enzyme being delivered as being, the mRNA being delivered as being translated, the enzyme is active and is doing what it needs to do in the liver.

If you put a lot of it in there, it goes in, will bind certain proteins, and cause some toxicities. And so this tells you you just have to manage the local concentration carefully at the time you administer it.

Enzyme being delivered as being the RMR RNA being liberty being translated the enzyme is active and is doing what it needs to do in the liver.

Thank you.

Our next question comes from Joel Beatty with Baird.

That chemistry effect can be enhanced by being a locteic acid, but the nocteic acid also gives you longer half-life and greater potency.

Your next question comes from Joel Beatty with Baird.

Hi, thanks for taking the questions.

So the question is, how do you balance those benefits of lactic acid versus the toxicity issues?

First I wanted to thank Dr. Zita.

Alright, thanks for taking the question.

Once patients start therapy, what's the rate of them sticking on therapy?

I think there are ways to look at that.

Thank you Peter.

Have you seen any drop-offs there?

And we think with the molecule we have and where it's targeting and the fact that, Only a milligram in a monkey can provide sufficient knockdown, which is well below what's been seen with other ASOs.

We think we have the glove of potency that the benefit of LNA can be obtained without risking the toxicity issues that happen from those more stable and those type of ASOs.

Patients start therapy.

Thanks, and just to follow up on the dose escalation, the progress there.

Thanks.

And then sticking on therapy have you seen any drop off Sir.

Well, as we've said, we have several patients have gone through five doses, which means they've gone through the four doses and have gone into maintenance.

We haven't really disclosed all the levels of dose titration. There has been titration.

And then also, for clean therapy and manufacturing, once the plant is operational next year, how does the capacity of that plant compare to the clinical pipeline programs you have in development?

And we'll put out all that detail on titration to what dose level and outcomes in all the patients at the mid year.

It's not really appropriate to start putting that out yet.

Then also for gene therapy manufacturing once the plant is operational next year, how does the capacity of that plant compared to the clinical pipeline programs you have in development.

But, As I said, multiple patients have reached five, which means they had four loading doses and then one dose of their maintenance regimen, which happens three months after the fourth dose.

Okay, so the persistence or compliance you're talking about was for Kris Vida?

Okay. So the persistence or compliance Youre talking about was for Christina.

Yes.

Yeah.

Yes, yes.

Chris Vita is in the...

Yes, okay.

Chris Vida is in the.

Your speed-up persistence is in the high 90 percentile range, so it's quite excellent.

Chris fee that persistence is is in the high 90 percentile range. So it is quite excellent.

Compliance is in the 90% plus range.

And compliance is in the 90% plus range so.

We see these are really good numbers for compliance and persistence so far.

Think part of the reason for that is patients can feel when they're on the drug and when they're not on the drugs if they miss a dose.

The phosphate will start to fall and they'll feel that effect of that and that just tells the need to get back on so we think that the fact that they can feel when their phosphate goes down it's probably a factor in why theyre staying compliant and once they get on the <unk>.

So we see these are really good numbers for compliance and persistence so far.

Want to stay on.

And I think part of the reason for that is patients can feel when they're on the drug and when they're not on the drug.

So thats.

So if they miss a dose, They the phosphate will start to fall and they'll feel that effect of that and that just tells them need to get back on so we think that the fact that they can feel when their phosphate goes down is probably a factor and why they're staying in compliant and once they get on they they want to stay on, So that's that.

That.

Gene therapy plant, it's about a 100,000 square foot plant.

Gene therapy plant.

100000 square foot plan it will have ultimately two suites independence.

It will have ultimately two suite.

Independent Suites that can run up to 2,000 liter production, and can turn over a number of runs a year.

Independent suites that can run up to 2000 liter production.

And we will turnover can turnover a number of runs a year it should be able to handle a significant fraction of our total though where plan was still to use a hybrid model with some contract manufacturing to supplement it.

It should be able to handle a significant fraction of our total, though our plan was still to use a hybrid model with some contract manufacturing to supplement it.

If we hit our marks and we get where we want to be.

Commercializing gene therapy, we have also the ability we have additional land that we have purchased next to the plan that we can add essentially doubled the plant up with two more suites that could make double the total capacity so with.

Within those range, we would have a good fraction of what we're doing on but we still are planning a hybrid model not a complete takeover of manufacturing.

If time goes push comes to shove, we need to we certainly would have the capacity ultimately to take on the programs. We have short of Duchenne, if the Duchenne program does well hit the clinic.

Entity product required for that program will be substantial and we will need more capacity.

Great, thank you.

Great. Thank you.

Our next question comes from Laura Chico with WETBUSH.

Thank you.

Our next question comes from Laura Chico with Wedbush.

Thank you very much for taking the question.

Thank you.

Thanks, very much for taking the question.

I guess I wanted to take a step back and for Amarin team.

How should we be thinking about the potential for longer term revenue guidance targets. Obviously casita you have considerable experience with this but youre approaching a transition point.

Just kind of wondering.

Our next question comes from Dajan Ha, Westifel.

What is the potential for longer range targets, and then maybe secondarily, how do you balance becoming profitable with continuing to expand your pipeline efforts at this point. So thank you very much.

I guess I wanted to take a step back.

Dagon, are you there?

And for Emil and team, how should we be thinking about the potential for longer term revenue guidance targets?

Operator, why don't we move to the next question?

Thank you Laura first of all I think our expectation is to see steady growth and the addition of the pieces to help also fill out the pipeline growth, but <unk> will be continuing to grow we believe along with the old drove which is doing really well that puts us on track with the three product and now adding it's Keith.

The hit.

Substantial revenue growth every year.

<unk>.

30, plus percent range or more.

Okay, our next question comes from Jeff Hung with Morgan Stanley.

So we feel very good about where that's taking us now with regard to our pipeline our.

Obviously, Kasita, you have considerable experience with this, but you're approaching a transition point.

Thanks for taking my question.

Just kind of wondering, What is the potential for longer range targets?

Can you talk about what we should expect to see from the Citrusmab and the UXO53 updates later this year?

Sure, so incitruzumab, We expect to have...

Almost 40 patients enrolled that will have gotten two months of dosing and what we'll have is information on their biomarker, the P1B biomarker, which were based on the historical data from the asteroid study in 90 patients, showed a nice correlation between their bone marrow density improvement, and the P1MP.

So you learn about safety, biomarker information at a high level, and then we'll talk about what our dosing strategy going forward in our plan to start phase three.

That's the Truth-O-Map.

And then maybe secondarily, how do you balance becoming profitable with continuing to expand your pipeline efforts at this point?

For O5-3, we're going to have basically single dose, single sending dose data, which we'll look at. Safety, of course, and as well as effects on glucose and other biomarkers and clinical assessments as well.

But because it's early and it's only single dose, we wouldn't expect to see dramatic clinical benefit at this point, but we're looking to see clinical activity in the biomarkers endpoints that would help us assess that the, Enzyme being delivered as being, the mRNA being delivered as being translated, the enzyme is active and is doing what it needs to do in the liver.

In development stage 68, the idea is that we want to create a certain size of spend around R&D that would generate a product filing on average every year. If you average it over two to three years and we think thats. When we can do it. So we don't want to keep growing R&D and definitely we are growing into the size.

We are at a peak right now because we have four programs in pivotal which is not normal and what our expectation is that over the next couple of years, we will start to plateau, and we will try to hold line there around that level of R&D spend and our expectation then the revenue continue to grow we will get operating leverage.

Our next question comes from Joel Beatty with Baird.

Jen and go profitable and that is our plan.

Our plan, though when you go profitable is to go profitable with a lot of products new products launching which we would expect in the next three or four years, which would put us in position to cross profitability.

Each profit, but to really fly far above it. So I think there's always a debate.

How much you want to spend versus how much you want to manage profitability. The key is when you spend spend well.

And to spend smartly and effectively and that's what we focus a lot on but right now we think the level of spend we're at is around the range, we want to be in the long run and as long as we continue to grow our revenues, we can well had to be a profitable company in the picture we see in the long range plan shows a whole series of products.

Generating revenue for us in a very robust diversified pipeline across mode, and therapeutic indication, which I think will make us.

Leading companies in the field of rare diseases.

So thank you very much.

Thanks, so much Jamie.

Thank you, Laura.

Thank you. Our next question comes from Nathan <unk> with Stifel.

First of all, I think our expectation is to see steady growth.

Hi, thanks for taking the questions.

And the addition of KISA is to help also fill out the pipeline growth.

First I wanted to thank Chris Vita.

Great. Good afternoon. Thanks for taking our question is im sorry about the earlier hiccup two questions from me one on Gtx 102, I wanted to ask you about sort of the confidence in the strength and the Gtx 102 IP.

But CRISPR-Vita will be continuing to grow, we believe, along with Dojovi, which is doing really well.

It looks like there is a little bit of an overlap on the sequence targets that Roche ion SME genetics are all kind of going after so I wanted to get your take on that and secondly, following up on the previous question.

Once patients start therapy, what's the rate of them sticking on therapy?

Going back to <unk>, you kind of prioritize a readily commercialize a ball product.

But I guess going forward, what kind of directionality would be enticing to you is it more commercialized about products or something like genetics, where you can take basically the entire ownership of a program. Thanks so much.

That puts us on track with the three products and now adding in KISA to hit substantial revenue growth every year in the, you know, 30 plus percent range or more.

Have you seen any drop-offs there?

And then also, for clean therapy and manufacturing, once the plant is operational next year, how does the capacity of that plant compare to the clinical pipeline programs you have in development?

Okay.

So with regard to.

Okay, so the persistence or compliance you're talking about was for Kris Vida?

The Gtx one to IP.

There is a distinct region within the AAP. This Texas A&M has the genetics license that we licensed part of our deal that is distinctive and separate from where I owned us and Roche operate distinct separate towards the five prime end of the <unk> message and the description we use involves.

That sequence plus we also are targeting not necessarily just introns, but conserve sequences and other aspects of what we do there are unique different which are important in achieving potency because the five prime and has a lot more potent at terminating the transcription of the Amazon RNA as well as destroying existing messages.

And Thats why we think that <unk> is uniquely.

Patented is powerful and important that is where the five prime end of the long end since message come from so that's why we think there is a separation of distinct <unk> why we did the deal originally because there's no way I would've planned to go head to head with Roche and Biogen ion is on a neurologic disease, except for the fact that.

So we feel very good about where that's taking us.

The group had an edge and they wanted to work with us and it looked like an opportunity we should take.

Yes.

So.

On the question of commercial versus.

Versus pipeline I think it is a fundamental question for you because I've heard people say why don't you buy $1 billion product, that's commercial well, yes, but how much do you have to pay for $1 billion product sorry, commercial. So obviously I don't think buying a product you know is building our products are already commercial is a good deal because I don't think theres any gain there is an arbitrage there is no way to make.

Money as a company, we can't do that with the premium on paying for the rest.

So when we buy later stage commercial products. They may be smaller niche products that are great for us where we can extract value with our unique.

Distribution system and team across the globe that is what regeneron wanted and we're able to use that skill to gain value from something with a $30 million upfront now <unk>.

Now, with regard to our pipeline, our plan here was not to run, to run about 68 clinical stage programs at the same time, Laura, and then not to grow beyond that, to be able to run 68 clinical stage.

Yeah.

Once we become commercial, it's separate, but if the, in development stage 68.

Chris Vita is in the chat.

The idea is that we want to create a certain size of spend around R&D that would generate a product filing on an average every year, if you average it over two or three years.

Grisfida Persistence is in the high 90 percentile range, so it's quite excellent.

<unk>, we can't make build a company on the smaller product we need to have some larger return products. Those are going to have to be earlier stage program, where then we have to take our developmental insight and skill to Pic design drive and execute in a reasonable timeframe. It takes something of uncertain value and turn it into something of value.

And we think that's when we can do it.

Compliance is in the 90% plus range.

And I think you would agree 20 owned our investment on a multibillion dollar opportunity that has now turned into summer.

Something of great value is the kind of investment we should be in as a biotech.

So we don't want to keep growing R&D indefinitely, we're growing to this size, we're at a peak right now, because we have four programs in Pivotal, which is not normal.

So we see these are really good numbers for compliance and persistence so far.

And what our expectation is, is that over the next couple years, we'll start to plateau.

And I think part of the reason for that is patients can feel when they're on the drug and when they're not on the drug.

And we will try to hold line there around that level of R&D spend.

And our expectation, then the revenue continue to grow, we'll get operating leverage and, and go profitable.

And that is our plan.

Our plan, though, when you go profitable is to go profitable with a lot of products, new products launching, which we'd expect in the next three or four years, which would put us in position to cross profitability, but not eat profit, but to really fly far above it.

So I think there's always a debate, how much you want to spend versus how much you want to manage profitability.

The key is when you spend well and to spend smartly and effectively, and that's what we focus a lot on, but right now we think the level of spend we're at is around the range we want to be in the long run, and as long as we continue to grow our revenue as we can, we'll head to be a profitable company.

And the picture we see in the long-range plan shows a whole series of products generating revenue for us in a very robust, diversified pipeline across mode and therapeutic indication, which I think will make us more profitable.

Add value and grow the value through our particular skills.

Hopefully that gives you a kind of a feel for our view.

Yes. It does thank you very much.

Thank you. Our next question comes from Yigal <unk> from Citigroup.

Hi, Thank you so much for taking the follow up just two clinical ones of milk.

Gene therapy plant, it's about a 100,000 square foot plant.

It will have ultimately two suite.

Great, thank you.

On the gene therapy programs I don't think I've ever asked you. This before but could you just clarify why for 401 and for 301 Youre doing a one to one randomization, but for Wilsons do op support two to one randomization. Thank you.

Independent Suites that can run up to 2,000 liter production, and can turn over a number of runs a year.

Our next question comes from Laura Chico with Wetbush.

It should be able to handle a significant fraction of our total, though our plan was still to use a hybrid model with some contract manufacturing to supplement it.

Thank you very much for taking the question.

If we hit our marks and we get where we want to be on commercializing gene therapy, we have also the ability, we have additional land that we have purchased next to the plant that we can add, essentially double the plant up with two more suites that could make double the total capacity.

So within those range, we have a good fraction of what we're doing on, but we still are planning a hybrid model, not a complete takeover of manufacturing.

But if time goes, push comes to shove, we need to, we certainly would have the capacity ultimately to take on the programs we have short of Duchenne. If the Duchenne program does well and hits the clinic, the quantity of product required for that program will be substantial and we'll need more capacity.

I guess I wanted to take a step back.

Yes, well in the.

301, a 401 originally we were going to do it.

Two to one and a 40 patient study and I, specifically decided we ought to go one to one to improve the power of the study and because I thought a 40 patient study with on the smaller side.

And the powering with steady is dependent on the size of the placebo arm and since we're looking at patients who are uncontrolled treatments.

We need to make sure we have an adequate power and so by.

Increasing and making one to one we're able to look at the existing treatment the others.

And for Emil and team, how should we be thinking about the potential for longer term revenue guidance targets?

Obviously, Kasita, you have considerable experience with this, but you're approaching a transition point.

Now for the Wilson program, if you noticed the total size of the program with much larger right.

So there's 27 people in the first part.

Just kind of wondering, What is the potential for longer range targets?

Six.

And then maybe secondarily, how do you balance becoming profitable with continuing to expand your pipeline efforts at this point?

Treated three placebo in each dose group 27 right.

Plus there will be $60 70 in the phase III part of the study so because of the study is much larger we can afford to do the two to one randomization still have enough power remaining by a large enough placebo group and because it has really good biomarker essentially urinary copper accretion. These are things, we can measure with great rely.

Ability and so we think the two to one works or that it's nicer to patients and we think the sign larger size of the study which is enabled by our better PCL manufacturing platform.

Puts us in position to be able to do a study that will cost less to make but it will treat more patients.

Okay, that's very logical thanks.

Just one on instruments I apologize if this has already been asked but just with respect to.

Still uncomfortable moving into a phase III for Angels.

Could you be a little more specific in terms of the point improvement that you'd like to see in CGI yet.

And across a minimum number of domains. So if you could provide a little quantitative commentary on sort of what point improvement you need to see and in how many domains youre aiming for it to feel good about taking the phase III.

Well, we had described before that for the purpose of dose titration, we were looking at at least two domains of plus two or better.

To me, meaning much improved or very much improved in the prior program. We had three patients that were much improved or a plus two and two patients that were very much improved.

So that gives you kind of a sense of what we might see but I would look at those of their trajectory amount of improvement over a period of time, the actual true differential in efficacy might depend on how long, we decided that we'll monitor and treat them, but I think that that level of change suggests to us.

Not long and essence message must be knockdown at UBS expression must be induced <unk> induced at maximally.

Doing it more doesn't matter you just need to give patients time to <unk>.

<unk> and improve their skills.

We are looking and if we were if we are running a study with CGI S. We'd want to see a plus two or better in our design for our phase III, that's what we'd want to see.

Wouldn't want to go with a program that was going to give you a plus 1% we'd want to make sure we get our.

Titration dosing such that we're looking at a much improved kind of score and I think patients deserve to have us do the work to make thats right I think it's within our grasp we know it can be achieved.

And we're close to where we need to be so I think it's a achieve.

Achievable to get to that level of efficacy with this program.

Great. Thanks, so much.

Thank you I'm showing no further questions at this time I would now like to turn the conference back to Joshua Heiko.

You know, one of the leading companies in the field of rare diseases.

So thank you very much.

Thanks so much, Emil.

Thank you, Laura.

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

Thank you.

First of all, I think our expectation is to see steady growth and the addition of KISA is to help also fill out the pipeline growth, but CRISPR-Vita will be continuing to grow, we believe, along with Dojovi, which is doing really well.

Our next question comes from Dajan Ha with Depot.

That puts us on track with the three products and now adding KISA to hit substantial revenue growth every year in the 30 plus percent range or more.

Great.

So we feel very good about where that's taking us.

Good afternoon.

Now, with regard to our pipeline, our plan here was not to run, to run about 68 clinical stage programs at the same time, Laura, and then not to grow beyond that, to be able to run 68 clinical stage.

Thanks for taking our questions.

Once we become commercial, it's separate, but at the.

And sorry about the earlier hiccup.

In development stage 68, the idea is that we want to create a certain size of spend around R&D that would generate a product filing on an average every year, if you average it over two or three years.

Two questions for me.

And we think that's when we can do it.

One on GTX 102.

So we don't want to keep growing R&D indefinitely, we're growing to this size, we're at a peak right now, because we have four programs in Pivotal, which is not normal.

Emil, I wanted to ask you about sort of the confidence and the strength in the GTX 102 IP.

And what our expectation is, is that over the next couple years, we'll start to plateau.

This concludes today's conference call.

It looks like there is a little bit of an overlap on the sequence targets that Roche, Ionis, and Genetics are all kind of going after.

And we will try to hold line there around that level of R&D spend.

So I wanted to get your take on that.

And our expectation, then the revenue continue to grow, we'll get operating leverage and, and go profitable.

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

And secondly, following up on the previous question, going back to FQISA, you kind of prioritize a readily commercializable product.

And that is our plan.

But I guess going forward, what kind of directionality would be enticing to you?

Is it more commercializable products or something like Genetics where you can take basically the entire ownership of a program?

So I think there's always a debate how much you want to spend versus how much you want to manage profitability. The key is when you spend well and to spend smartly and effectively, and that's what we focus a lot on.

Thanks so much.

But right now, we think the level of spend we're at is around the range we want to be in the long run, and as long as we continue to grow our revenue as we can, we'll head to be a profitable company.

Okay, so with regard to...

The GTX-12 IP, there is a distinct region within the IP that Tex A&M has, a GenX license that we license as part of our deal, that is distinctive and separate from where Ionis and Roche operate.

You know, one of the leading companies in the field of rare diseases.

Distinct and separate towards the 5 prime end of the NSF message, And the description we use involves that sequence, plus we also are targeting not necessarily just introns, but conserved sequences and other aspects of what we do that are unique and different, which are important in achieving potency, because the 5' end is a lot more potent at terminating the transcription of the antisense RNA, as well as destroying existing messages. And that's why we think that 5' end that is uniquely patented is powerful and important.

Thanks so much, Emil.

That is where the 5' end and the long antisense message come from.

Thank you.

So that's why we think there's a separation.

Our next question comes from Dajan Ha with Depot.

A distinct one is why we did the deal originally, because there's no way I would have planned to go head-to-head with Roche and Biogen Ionis on a neurologic disease, except for the fact that the group had an edge, and they wanted to work with us, and it looked like an opportunity we should take.

Great.

So on the question of commercial versus, versus Pipeline.

Good afternoon.

I think it's a fundamental question for you because I've had people say, why don't you buy a billion-dollar product that's commercial?

Thanks for taking our questions.

Well, yes, but how much do you have to pay for a billion-dollar product that's already commercial?

And sorry about the earlier hiccup.

So obviously, I don't think buying a product you know is a billion-dollar product that's already commercial is a good deal because I don't think there's any gain.

Two questions for me.

There's an arbitrage.

One on GTX 102.

There's no way to make money as a company.

Emil, I wanted to ask you about sort of the confidence and the strength in the GTX 102 IP.

We can't do that with the premium I'm paying for, the rest.

It looks like there is a little bit of an overlap on the sequence targets that Roche, Ionis, and Genetics are all kind of going after.

So, when we buy a later stage commercial product, they may be smaller niche products that are great for us, where we can extract value with our unique distribution system and team across the globe, that is what Regeneron wanted, and we're able to use that skill to gain value from something with the $30 million up front.

So I wanted to get your take on that.

Angeman, we can't make build a company on the smaller products, we need to have some larger return products.

And secondly, following up on the previous question, going back to FQISA, you kind of prioritize a readily commercializable product.

Those are going to have to be earlier stage programs, where then we have to take our developmental insight and skill to pick, design, drive, and execute in a reasonable timeframe to take something of uncertain value and turn it into something of value.

But I guess going forward, what kind of directionality would be enticing to you?

And I think you would agree that a $20 million investment on a multi-billion dollar opportunity that is now turned into something of great value is the kind of investment we should be in as a biotech.

Is it more commercializable products or something like Genetics where you can take basically the entire ownership of a program?

But adding a late-stage commercial product that leverages our operating revenue and takes advantage of our rare disease skills commercially is also a good deal.

Thanks so much.

So if you see a late-stage deal, it's more likely to be smaller niche and perfect fit for us.

Okay, so with regard to...

And if it's earlier stage, we might do some things that are higher risk, higher return, but where we can add value and grow the value through our particular skills.

The GTX-12 IP, there is a distinct region within the IP that Tex A&M has, a GenX license that we license as part of our deal, that is distinctive and separate from where Ionis and Roche operate.

Hopefully that gives you kind of a feel for our view.

Distinct and separate towards the 5 prime end of the NSYNC message, And the description we use involves that sequence, plus we also are targeting not necessarily just introns, but conserved sequences and other aspects of what we do that are unique and different, which are important in achieving potency, because the 5'-end is a lot more potent at terminating the transcription of the antisense RNA, as well as destroying existing messages. And that's why we think that 5'-end that is uniquely patented is powerful and important.

Yep, it does.

That is where the 5'-end and the long antisense message come from.

Thank you very much.

So that's why we think there's a separation, a distinct one.

Thank you.

It's why we did the deal originally, because there's no way I would have planned to go head-to-head with Roche and Biogen Ionis on a neurologic disease, except for the fact that the group had an edge and they wanted to work with us, and it looked like an opportunity we should take.

Our next question comes from Yigal Nochomovitz from Citigroup.

So on the question of commercial versus, versus Pipeline.

Hi.

I think it's a fundamental question for you because I've had people say why don't you buy a billion dollar product that's commercial?

Thank you so much for taking the follow-up.

Well, yes, but how much do you have to pay for a billion dollar product already commercial?

Just two clinical ones, Emil.

So obviously, I don't think buying a product you know is a billion dollar product already commercial is a good deal because I don't think there's any gain.

On the gene therapy programs, I don't think I've ever asked you this before, but could you just clarify as to why for 401 and for 301, you're doing a one-to-one randomization, but for Wilson's, you opted for a two-to-one randomization?

There's an arbitrage.

Thank you.

There's no way to make money as a company.

Yes, well, in the 31401, originally, we were going to do a two to one and a 40 patient study.

We can't do that with the premium on paying for the rest.

And I specifically decided we ought to go one to one to improve the power of the study.

So, when we buy a later stage commercial product, they may be smaller niche products that are great for us, where we can extract value with our unique distribution system and team across the globe.

And because I thought a 40 patient study was on the smallish side, and the powering of the study is dependent on the size of the placebo arm.

That is what Regeneron wanted, and we're able to use that skill to gain value from something with the $30 million up front.

And since we're looking at patients who are on control treatments.

Now...

We need to make sure we have an adequate power.

Angeman, we can't make build a company on the smaller products, we need to have some larger return products.

And so by increasing and making it one-to-one, we're able to look at the existing treatment and the others.

Now, for the Wilson program, if you notice, the total size of the program is much larger, right?

So there's 27 people in the first part, six.

But adding a late-stage commercial product that leverages our operating revenue and takes advantage of our rare disease skills commercially is also a good deal.

And we think the largest size of study, which is enabled by our better PCL manufacturing platform, puts us in position to be able to do a study that will cost less to make, but it will treat more patients.

So if you see a late-stage deal, it's more likely to be smaller niche and perfect fit for us.

Okay, yeah, that's very logical.

And if it's earlier stage, we might do some things that are higher risk, higher return, but where we can add value and grow the value through our particular skills.

Thanks.

Hopefully that gives you a kind of a feel for our view.

And then just one on Angelman's, apologies if this has already been asked, but just with respect to, you know, feeling comfortable moving into a phase three for Angelman's, could you be a little more specific in terms of the point improvement you'd like to see in CGI-AS and across a minimum number of domains?

Yep, it does.

So if you could provide a little quantitative commentary on sort of what point improvement you need to see and in how many domains you're aiming for, to feel good about taking the phase three.

Thank you very much.

Thank you.

Well, we had described before that for the purpose of dose titration, we were looking at at least two domains of plus two or better, plus two meaning much improved or very much improved. In the prior program, we had three patients that were much improved or plus two and two patients that were very much improved.

Our next question comes from Yigal Nochomovitz from Citigroup.

So that gives you kind of a sense of what we might see, but I would look at those as a trajectory, the amount of improvement over a period of time, the actual true differential and efficacy might depend on how long we decide to monitor and treat them.

Hi, thank you so much for taking the follow-up.

But I think that that level of change suggests to us, that the not long and the sense message must be knocked down and that you be the expression must be induced.

Just two clinical ones, Emil.

And once you've induced it maximally.

Doing it more doesn't matter, you just need to give patients time to develop and improve, We are looking, and if we were running a study with CGIAS, we'd want to see a plus two or better.

Thank you.

In our design for our phase three, that's what we'd want to see.

Yes, well, in the 31401, originally, we were going to do a two to one in a 40 patient study.

We wouldn't want to go with a program that was going to give you a plus one, we'd want to make sure we get our, Titration dosing such that we're looking at a much improved kind of score and I think patients deserve to have us do the work to make that right.

And I specifically decided we ought to go one to one to improve the power of the study.

I think it's within our grasp.

And because I thought a 40 patient study was on the smallest side, And the powering of the study is dependent on the size of the placebo arm.

We know it can be achieved and we're close to where we need to be. So I think it's achievable to get that level of efficacy with this program.

And since we're looking at patients who are on controlled treatments.

Great, thanks so much.

We need to make sure we have an adequate power.

Thank you.

And so by increasing and making it one-to-one, we're able to look at the existing treatment and the others.

I'm showing no further questions at this time.

Now, for the Wilson program, if you notice, the total size of the program is much larger, right?

I'd now like to turn the conference back to Joshua Higa.

So there's 27 people in the first part, six.

Thank you.

Tazeen Ahmad, Yigal Nochomovitz, Christopher Raymond, Gena Wang, Anupam Rama, and we think the largest size of study, which is enabled by our better PCL manufacturing platform, puts us in position to be able to do a study that will cost less to make, but will treat more patients.

This concludes today's call.

Okay, yeah, that's very logical.

If there are additional questions, please contact us by phone or at IR at Ultragenyx.com.

Thanks.

Thank you.

So if you could provide a little quantitative commentary on sort of what point improvement you need to see and in how many domains you're aiming for, to feel good about taking the phase three.

Thank you.

But I think that that level of change suggests to us, that the not long and the sense message must be knocked down and that you be the expression must be induced.

And once you've induced it maximally, Doing it more doesn't matter, you just need to give patients time to develop and improve their skills.

We are looking, and if we were running a study with CGI-AS, we'd want to see a plus two or better in our design for our phase three.

That's what we'd want to see.

We wouldn't want to go with a program that was going to give you a plus one, we'd want to make sure we get our, Titration dosing such that we're looking at a much improved kind of score, and I think patients deserve to have us do the work to make that right.

I think it's within our grasp. We know it can be achieved, and we're close to where we need to be, so I think it's achievable to get that level of efficacy with this program.

Great, thanks so much.

Thank you.

I'm showing no further questions at this time.

I'd now like to turn the conference back to Joshua Higa.

Thank you.

This concludes today's call.

If there are additional questions, please contact us by phone or at ir at ultragenyx.com.

Thank you.

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