Q2 2021 Ultragenyx Pharmaceutical Inc Earnings Call

Okay.

Operator: Good day, and thank you for standing by. Welcome to the Second Quarter 2021 Financial Results and Corporate Update Conference Call.

Good day, and thank you for standing by welcome to the second quarter 2021 financial results and corporate update conference call. At this time all participants are in a listen only mode. After the speaker's presentation. There will be a question and answer session and you ask the question during the session you will need.

Operator: This time all participants are on a list in most cases. After the speaker is

Operator: After the presentation, there will be a question and answer session.

Operator: As a question during that session, you will need to press star 1 on your

The press Star 1 and your telephone. Please note the limit yourself to 1 question with the follow up and if you require any further assistance. Please press star zero.

Operator: Please note to limit yourself to one question with a follow-up. And if you require any further assistance, press star zero. I would now like to hand the conference over to your first speaker today, Joshua Higa, Director

I'd now like to hand, the conference over to your first speaker today, Joshua Higa director of Investor Relations. Thank you. Please go ahead.

Operator: Joshua Higa, Director of Investor Relations. Thank you. Please go ahead.

Good afternoon, and welcome to the <unk>.

Joshua Higa: Good afternoon, and welcome to the Ultrogenic Financial Results and Corporate Update Conference Call for the second quarter of 2021. We've issued a press release detailing our financial results, which you can find on our website at ultrogenics.com. I am Joshua Higa, Director of Investor-Ral nation. Joining me on this call are Amel Cacch, Chief Executive Officer and President, Camille Bidrosian, Chief Medical Officer, and Eric Harris, Chief Commercial Officer. Marty Deer, our chief financial officer, had an unavoidable flight delay and is not able to join us on today's call.

Ultra <unk> financial results and corporate update conference call for the second quarter 2021.

We've issued a press release detailing our financial results, which you can find on our website at ultra <unk> Dot Com I'm, Joshua and he got director of Investor Relations joining.

Joining me on this call are Emil Caucus, Chief Executive Officer, and President Camille Bedrosian, Chief Medical Officer, and Erik Harris, Chief Commercial officer.

Marty <unk>, our Chief Financial Officer had and unavoidable flight delays and is not able to join us on today's call.

Joshua Higa: I would like to remind investors that this call will include forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to: The types of statements identified as forward-looking in our 2020 annual report on Form 10K that was filed on February 12, 2021, our quarterly report on Form 10Q that will be filed soon, and our subsequent periodic reports filed with the SEC, which will all be available in the investor section on our website.

I would like to remind investors that this call will include forward looking statements within the meaning of the safe Harbor provisions of the private Securities Litigation Reform Act of 1995, including but not limited to the types of statements identified as forward looking and our 2020 and report on form 10-K that was filed on February 12.2021.

Our quarterly report on form 10-Q that will be filed soon and our subsequent periodic reports filed with the SEC, which will all be available on our and the investors section on our website.

Joshua Higa: These forward-looking statements represent our views only as of the date of this call and involve substantial risks and uncertainties, including many that are beyond our control. Please note that actual results could differ materially from those projected in any forward-looking statement. For a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward-looking statements, as well as risks related to our business, please see our periodic reports filed with the SEC. I'll now turn the call over to Amy.

These forward looking statements represent our views only as of the date of this call and involve substantial risks and uncertainties, including many that are beyond our control.

Please note actual results could differ materially from those projected and any forward looking statement for further description of the risks and uncertainties that could cause actual results to differ materially from those expressed and the forward looking statements as well as risks related to our business. Please see our of periodic reports filed with the SEC I'll now turn the call over to him.

Amy: Thanks, Josh, good afternoon, everyone. I want to quickly reflect on our progress mid-year and note that we're approaching a period of significant execution on our clinical programs in the second half of this year. For those who are newer to our story, we're a diversified global commercial rare disease company with three products approved for four indications. We now have one of the broadest clinical portfolios among rare disease companies in terms of modalities and indications, and one of the most prolific late-stage pipelines of both gene therapy and rare disease. This is testament to our ability to identify great signs, do effective deal transactions, and drive that work forward in the development of our first years, 11 years as a company.

Thanks, Josh and good afternoon, everyone I wanted to quickly reflect on our progress mid year and note. The we're approaching a period of significant execution of our clinical programs and the second half of this year for that.

Those who are newer to our story, we're a diversified global commercial rare disease company with 3 products approved for for indications.

We know of 1 of the broadest clinical portfolios among rare disease companies in terms of modalities of and indications and 1 of the most prolific late stage pipelines of both gene therapy and rare disease.

And the Testament of our ability to identify great science do affect of deal transaction that drive that work forward and development of our first years 11 years and for the company.

We are now on track to initiate for pivotal clinical trials over the second half of this year.

Amy: We are now on track to initiate four pivotal clinical trials over the second half of this year, and these include phase 3 studies for two of our gene therapy programs, DTX 401 and DTX 301 in GSD 1A and OTC, respectively, to a seamless phase-2-123 study for gene therapy target UX-701 in Wilson disease, and finally, a phase 23 pivotal study for UX143 in osteogenesis in Profecta. Additionally, we will begin our first MRRNA therapy in a Phase 1-study for UX-53 and GSD3.

And these include phase.

Phase III studies for 2 of our gene therapy programs D. T X for 1 of the D. T X 301, and G. S. D..1 8 and O T C respectively.

2 of seamless phase 123 study for gene therapy target UX, 7 and 1 in Wilson disease.

Finally, our phase 3 pivotal study for you, it's 1 for 3 and the osteogenesis imperfecta.

Additionally, we will begin our first mrna therapy of phase 1.2 study for U S O 5.3 and GST 3.

Amy: Finally, GtX 102 developed by our partner genetics will now be back in the clinic treating angels and patients again. I'll begin with the Angelmo program, then I'll summarize their clinical and commercial progress before handing it over to the team to provide more details. As previously announced, in May and June, Health Canada and the UK's MHRA approved a modified clinical protocol to begin dosing pediatric patients with Angerman Syndrome in those regions. These approvals followed review by both regulatory bodies of the clinical data on the first five patients in the U. As well as abundant non-clinical data.

Finally, gtx, 1 or 2 developed by our partner genetics will now be back in the clinic treating angel and patients again.

I'll begin with the annual program and then I'll summarize our clinical and commercial progress before handing it over to the team and provide more details.

With the previously announced in May and June and Health, Canada, and the U K and nature of approved and modify clinical protocol to begin dosing pediatric patient with the Angelman syndrome and those regions.

These approval followed review by both regulatory bodies of the clinical data and the first 5 patient of the U S as well as abundant and non clinical data.

Amy: The U.S. agreed to move forward based on both the promising activity seen at the first lower dose of GTX-2 before any signs of serious adverse events had occurred, and the extremely high medical need across 60,000 patients and their families. We're now working closely with our partners in next to wrap up the remaining logistical details to get sites enrolling and dosing patients.

The agreed with moving forward based on both the promising activity seen at the first lower doses of Gtx, 1 and 2 before any signs of serious adverse event had occurred and the extremely high unmet medical need across the 60000 patients and their families.

We're now working closely with our partners and the next to wrap up the remaining logistical details to get sites enrolling and dosing patients.

And the U S. We continue to make progress and our discussion with the FDA for zoom and the study.

Amy: We continue to make progress in our discussions with the FDA for resuming the study. Those discussions have been productive, and we have received agreement from the agency on a dose and administration plan for naive patients. The agency has requested us to bolster the protocol with some specific additional neurological assessments and documentation to verify the safety of the GTX-2 during steady conduct and to manage the study closely. We'll make further simple adjustments to the protocol based on the feedback in order to get clearance to resume the study in the U. At this time, the FDS asked us to hold back on retreating the previously treated patient.

Those discussions have been productive and we ever see of the green from the agency on a dose and administration plan for naive patients.

The agency has requested us to bolster the protocol with some specific additional neurological assessments and documentation.

Verify the safety of the Gtx, 1 and 2 during the study conduct and the manager studied closely.

We will make further simple adjustments of the protocol based on the feedback and already get clearance truth, and the study and the U S.

At this time, the FDA has asked us to hold back on retreating the prior treated patients.

Amy: As we have known before, we plan to provide a preliminary data update from some patients treated with GTX102 either in XUS or in the U.S. by the end of the year. The amount of data may be limited based on the timing; we expect to treat the first cohort of patients. Overall, we are enthusiastic about the process for treating Engerman with GTX 102 based on everything we know today.

As he of note before we plan to provide a preliminary data updates and some patients treated gtx, 1 or 2 either ex U S or in the us by the end of the year.

The amount of day to May be limited based on the timing, but we expect to treat the first cohorts of patients.

Overall, we are enthusiastic about the prospects for treating the instrument Gtx 1 of 2 based on everything we know today, we're looking forward to getting this treatment developed.

Amy: We're looking forward to getting this treatment developed. Shifting to our gene therapy franchise, who've completed all of the known requirements to initiate three pivotal studies in GST 1A with DTX 401, ODC deficiency with DTX301, and Wilson disease with UX701. At the ASGCT conference in May, we announced positive longer-term data from the DTX 401 Phaseone two study showing a 100% response rate across all nine patients treated and a durable response extending to two and a half years.

Shifting to our gene therapy franchise, we've completed all of the known requirements to initiate 3 pivotal studies and GST and <unk> with D. T X for O..1 OTC deficiency. The D. T O 301, and Wilson disease with U S..7 of 1.

And at the a F. G C. T conference in May we announced positive longer term data from the D. T X for 1 phase 1.2 studies, showing and 100% of response rate across all 9 patients treated and a durable response extending to 2 and a half years.

Amy: Similarly, we shared positive long-term data from the DTX 301, Phase 1-study, which showed a response from all three patients at the Phase 3 dose, and total six of nine responders in the first three cohorts of patients enrolled. These patients maintain or improve the response up to three years following treatment. Teams are in study start-up for the Pidstit for Pidstit, and we expect them to get going soon. Our proprietary commercial quality HeLa manufacturing platform will be the basis for the next generation of ultra-ex gene therapy products, starting with our program for Wilson disease and extending to our pre-clinical program for Duchenne, Muscatistrophy, and CDKL5 deficient, a neurodevelopmental disorder.

Similarly, we shared positive long term data from the D. T O 301 phase 1.2 study the showed a response from all 3 patients at the phase II dose and total of 6 of 9 responders and the first 3 cohorts of patients enrolled.

And these patients maintain or improve the response up to 3 years following treatment.

The teams there and steady startup mode for the pivotal studies and we expect them to get going soon.

Our proprietary and commercial quality of Hela manufacturing platform will be the basis for the next generation of Ultra and X gene therapy products, starting with a program for Wilson disease, and extending to our preclinical programs for Duchenne muscular dystrophy and C. D kill of 5 deficiency and <unk>.

The road about mental disorder.

Amy: These latter two preclinical programs represent our first non-liver targeted gene therapies and address a much larger patient population. We will provide updates on these programs later this year. Beyond our gene therapy work, we mean on track to initiate two additional clinical programs this year. One is Ux143 or Satruzumab, our recently licensed antibody for OUGY imperfect or OI. Our partner has already generated promising results in adults with OI showing substantial improvement in bone density.

The latter 2 preclinical programs represent our first non liver targeted gene therapies and the rest of much larger patient populations.

We will provide updates and these programs later this year.

Beyond the gene therapy work with me and on track to initiate 2 additional clinical programs. If you're 1 of the UX 1 for 3 or the truth of the Mab. Our recently licensed the antibody for osteogenesis Imperfecta R O I.

And there is already generate promising results in adults with the O I showing substantial improvement bone density.

Amy: Based on our review of the science, both clinical and non-clinical, we are convinced that the handspin of bone production via the antisylostin mechanism will improve bone mental density in a productive manner that will improve bone strength in patients with OI by making new bone right where bone stress is needed and be superior then to purely antoresortive actions, for example, dysphosphonate.

Based on all of our review of the science, both clinical and non clinical we are convinced that the Hansen of bone protection by of the anti school roster and mechanism.

And we'll improve bone mineral density and a productive manner that will improve bone strength and patients with O I and by making new bone right, we're bound stress and if needed and the superior than 2 purely enter resort for the actions for example of this loss and H.

Amy: This should decrease fracturing and potentially prevent the deformation of the spine and bones that comes with repeated fractures early in life, especially in patients with type 3 or type 4OI. The clinical study will focus on pediatric and young adult patients that have frequent fractures. We are planning the initiation of a phase two, three study for this population by the end of the year. The other program is UXO53, an MRNA program for collection storage disease type 3.

This should decrease for action, so potentially prevent the deformation of spine and bones and comes with repeated fractures early in life, especially and the patients with type 3 or type for O I.

Yeah.

The clinical study will initiate will focus on pediatric and young adult patients that have frequent fractures and we are planning the initiation of the phase 3 study for this population by the end of the year.

The other program is the UX <unk> 3 and the mrna program for collection and storage. These type 3.

Amy: This first MRNA program for our license with our tourist therapeutics is also expected to enroll a phase one-two study by year end. Now turning to our commercial programs, we had another solid quarter with significant revenue increases from Q1 and 2020, with progress across the globe. Chris Krista particularly continues on a strong growth trajectory even as we enter the fourth year from its initial approval in 2018. Continued uptake is driven by both North America and Latin America. In North America, the adult exhalation population is a major driver, in line with our expanded patient ID and broader physician outreach efforts.

The first mrna program for a license with Arcturus Therapeutics and is also expected to begin enrolling our phase 1.2 study by year end.

Now turning to our commercial programs, we had another solid quarter with significant revenue increases from Q1, and 2020 with progress over the globe.

The truth crispy and it particularly continues on the strong growth trajectory, even as we enter the fourth year from its initial approval in 2018.

The continued uptake is driven by both North America, and Latin America and the.

North America penetration and the adult <unk> population of the major driver in line with our expanded patient idea and broader physician outreach efforts.

Amy: In Latin America, our team's efforts in supporting patient reimbursement have helped drive increased volume and revenue, and patients are staying on Krasita once they start and are compliant with their regimen. That is a testament to how much it helps patients with XLH. We also have a number of multi-generational families on Chris Feta now, and there's nothing better than to get notes from families, comments on how much their lives across generations have changed

And Latin America, our team's efforts and supporting patient reimbursement have helped to drive increased volume and revenue and patients are staying on course eat of 1 started and compliant with the regimens.

That is a testament to how much it helps patients with the actual age.

We also of a number of multi generational families on chris' feed and now and there's nothing better than the get notes from families comedy and how much of their lives across generations have changed.

Amy: Chris Vita is a paradigm shift in that's LH treatment, and we're happy to be at the forefront in making this happen. Our strong launch with Krasid has been followed by our successful launch, Jolv, which has now been on the market for about a year. Our team established great momentum, identifying patients, securing reimbursement coverage, and facilitating new start forms. The Strong Start shows how much a new option was needed for LC-S-O-D, and tells us that Dojolves will also represent a paradigm shift in the management of LCFOD. I'll now turn the call over to Eric to discuss our commercial progress in the core.

Kristina the paradigm shifts and that's the latest treatment, we're happy to be at the forefront of making this happen.

Our strong launch with Crazy and it's been followed by our successful launch those royalty, which has now been on the market for about a year.

Our team of established great momentum identifying patients and securing reimbursement coverage. The facilitator new start forms the strong start shows how much of new option was needed for L. C. S E O D and.

And tells us that the Shelby will also represent a paradigm shift and the management L. P. S O D.

I'll now turn the call over to Eric to elaborate and our commercial progress in the quarter.

Thank you Emil and good afternoon, everyone before I get into the details of the commercial performance for the quarter.

Eric: Thank you, Amel, and good afternoon, everyone. Before I get into the details of the commercial performance for the quarter, I'd like to thank all of the teams for their work and dedication during what are still uncertain times. While most states have reopened, they have shown an ability to adapt and overcome challenges within this new environment of conducting business.

And thank all of the teams for their work and dedication during what are still uncertain times.

While most states have reopened and the teams have shown an ability to adapt and overcome challenges with this within this new environment of conducting business.

For speed of had another strong quarter growing 6% versus the first quarter of 2021 and 38% over the second quarter of 2020.

Eric: Chris Vita had another strong quarter, growing 6% versus the first quarter of 2021 and 38% over the

Within the North American region second quarter revenue grew 15% versus the prior quarter as the seasonal reimbursement of effects normalized.

Eric: and 38% over the second quarter of 2020. Within the North American region, second quarter revenue grew 15% versus the prior quarter as the seasonal reimbursement effects normalized. First of revenue in Latin America declined quarter over quarter, but this is driven by an uneven ordering pattern and is not reflective of the underlying demand.

For speed of revenue and Latin America declined quarter over quarter, but this is driven by and uneven ordering patterns and is not reflective of the underlying demand given.

Given the strong demand and execution, we've seen and the first half of the year. We continue to affirm the 2021guidance range. We previously provided for revenue and ultra genetics territories of $180 million to $190 million.

Eric: Given the strong demand and execution we have seen in the first half of the year, we continue to affirm the 2021 guidance range we previously provided for revenue and ultrigenic territories of $180 to $190. In the United States, we are continuing to make inroads beyond major endocrinology and metabolic bone centers into community clinics where we are finding more and more adult patients. Early on in the launch, adults made up 40% of the patients treated with Chris Vita.

And the United States, we are continuing to make inroads beyond major endocrinology and metabolic bone centers and into the community clinics, where we're finding more and more of adult patients early on and the and the launch of adults made up 40% of the patients treated with Christina <unk>.

Good day as the total number of patients on therapy has grown significantly. So too has the portion of adults who have received per sweetener. We are now at approximately a 50.50 split between adults and peds on per suite of therapy, mainly driven by the work the team has done and the small harder to reach.

Eric: Today, as the total number of patients on therapy has grown significantly, so too has the portion of adults who have received Chris Vita. We are now at approximately a 50-50 split between adults and PEDs on Chris Vita therapy, mainly driven by the work the team has done in the small, harder-to-reach community clinic. As the teams leverage and expand upon investments that were made over the last year, we are confident we will continue to find more patients with XLH and TIO who could benefit from Chris Fita, shifting quickly to Latin America.

Community clinics as the teams leverage and expand upon investments that were made over the last year. We are confident we will continue to find more patients with <unk> and tio, who could benefit from Christina.

Shifting quickly to Latin America, we continue to see growing demand for Chris Vida across this region as is typical for reimbursement approvals and Latin American countries can take some time.

Eric: Chris Vita across this region received, as is typical, full reimbursement approvals.

Eric: Reimbursement approvals in Latin American countries can take some time, but the base of patients continues to expand as more are granted injunctions and gain access to named patient cells. In Columbia, we recently received regulatory approval for treatment of XLH and adult and pediatric patients one year of age and older. Patients had been on therapy through named patient programs, but this will significantly streamline the process for patients to respond.

But the base of patients continues to expand as more of a branded injunctions and gain access to named patient sales and.

Colombia.

We recently received regulatory approval for treatment of XL, H, and adult and pediatric patients 1 year of age and older pace.

Patients had been on therapy through named patient programs, but this will significantly streamline the process for patients to receive reimbursement reimbursed therapy.

Eric: for patients to receive reimbursed therapy.

And Brazil, we are and the final stages of negotiating for reimbursement and in the meantime continue to receive orders for the Minister Ministry of health to support the patients who have been granted and injunction to receive this therapy.

Eric: In Brazil, we are in the final stages of negotiating full reimbursement, and in the meantime, continue to receive orders from the Ministry of Health to support the patients who have been granted an injunction to receive this therapy. Now, we turn to Jovi, which was approved for the treatment of long-chain fatty acid fatty acid oxidation disorders, or LCFLD, by the FDA in June 2020 and by Health Canada in February 2021. Recall, there are an estimated 2, to 3,500 patients in the U. with LC-A-A-D. As of the end of the second quarter, we have received approximately 270 completed starter forms.

Turning now to the jewelry.

Which was approved for the treatment of long chain fatty acid.

Fatty acid oxidation disorders, or LC <unk> D by the FDA and June 2020, and by Health, Canada and February 2021.

Recall, there are and estimated 2000 to 3005 hundred patients and the us with L. C. S E O D.

As of the end of the second quarter. We have received approximately 270 completed start forms the.

Eric: This represents significant penetration into the prevalent patient population at this point in the lawn. These star forms have come from more than 130 unique prescribers of the Joby, with approximately half having written more than one prescription.

This represents significant penetration and so the prevalent patient population at this point of the launch of <unk>.

The start forms of come from more than 130 unique prescribers of the jewelry with approximately half having written more than 1 prescription.

Eric: This has led to approximately 220 patients on reimbursed commercial therapy

This has led to approximately 220 patients on reimbursed commercial therapy and continues to speak to the broad interest we're seeing from the physician community and strong support from payers.

Eric: and continues to speak to the broad interests we are seeing from the physician community and strong support from payers. As of the end of June 2021, payers are providing broad coverage for patients with LCFD. The time from completed star forms to reimbursement for therapy continues to outpace what we saw at a similar point in the CRISVita launch. It is great to see so many patients in the U. with LCFAODs quickly and successfully navigating their insurance policies. Outside of the U.S., there are a number of patients who

As of the end of June 2021, payers of providing broad coverage for patients with LC <unk>.

The time from completed start forms to reimbursed therapy continues to outpace what we saw at a similar point and the crispy the launch.

It is great to see so many patients in the us with <unk> the quickly and successfully navigating their insurance policies.

Outside of the US. They are there are a number of patients who have received the Dolby through named patient and early access programs. We are continuing to work with regional regulate regulators to gain full approval to treat all patients who could benefit from the jobin.

Eric: have received the Joby through a named patient

Eric: and Early Access programs. We are continuing to work with regional regulators to gain full

Eric: to treat all patients who could benefit from DeJ.

Eric: benefit from DeJov. In Brazil, we have had positive discussions with the Ministry of Health and are hopeful that the review process will be hopeful about the review process with this agent. Looking forward to the second half of the year, the commercial and field teams will continue leveraging many of the tactics that were developed last year. We have learned how to adapt to this new environment and will continue to find more and more patients who could benefit from Chris Vita, Di Jovey, and Mepsevi. With that, I'll turn the call back to Joshua to share the financial results.

And Brazil, we have had positive discussions with the ministry of health and.

And are hopeful.

That the review process.

Hopeful about the review process with this agency.

Looking forward to the second half of the year, the commercial and field teams will continue leveraging many of the tactics that we developed last year, we have learned how to adapt to this new environment and we'll continue to find more and more patients who could benefit from Chris feeder.

Dolby and <unk> with that I'll turn the call back to Joshua to share of the financial results.

Thanks, Eric we issued a press release earlier today that included of financial update, which I will briefly summarize company revenue.

Joshua Higa: We issued a press release earlier today that included a financial update, which I will briefly summarize. Company revenue for the quarter ending June 30, totaled $87. Chris Rita revenue in Ultrogenics territories was $44.7 million, including $41.8 million from the North American Profit Share Territory and net product sales of $2.9 million in other regions. Total Royalty revenue related to the sales of Chris Vita and the European territory was 4.

<unk> for the quarter ending June 32021 totaled 87.0 million.

Chris Reed of revenue and ultra <unk> territories was $44.7 million, including $41.8 million from the North American profit share territory, and net product sales of $2.9 million and other regions.

Total royalty revenue related to the sales of Christina and the European territory was $4.9 million.

Joshua Higa: As a reminder, ordering patterns in Latin America will vary from quarter to quarter. In the first quarter of 2021, we received a large stocking order from Brazil's Ministry of Health to support patient demand in that region. We are confident revenue from this region will continue to grow over time driven by strong underlying demand, but ordering patterns will be uneven in the near term as we work through the reimbursement process.

As a reminder, ordering patterns and Latin America will vary from quarter to quarter and the first quarter 2021, we've received a large stocking order from Brazil's Ministry of health to support the patient demand and that region.

We are confident revenue from this region will continue to grow over time, driven by strong underlying demand for ordering patterns will be uneven and the near term as we work through the reimbursement process.

Joshua Higa: Dejolvie revenue for the quarter was $10. As we have noted before, we will not be providing revenue guidance for Dejolvi in these first quarters of line. We believe the metrics Eric discussed better describe the success we are seeing so far.

The jewelry revenue for the quarter was 10.0 million.

As we have noted before we will not be providing revenue guidance for <unk> and these first quarters of launch we believe the metrics Eric discussed better describes the success we are seeing so far.

Joshua Higa: Mepsevi revenue for the second quarter was $5. We expect these revenues may modestly increase over time. Second Quarter 2021 revenue also includes $22. related to Tech Transfer as part of our strategic manufacturing partnership with Daiji Sankey around our HILA, PCL, and HEC2-93 technologies Through the rest of the year, through the rest of this year, the revenue recognition will taper significantly as the tech transfer activities come to a close. Additional details on this revenue recognition can be found in our annual and quarterly reports filed with the SECC. Our total operating expenses for the quarter were $169, which included research and development.

And of savvy revenue for the second quarter of 2021 was $5.4 million. We expect these revenues may modestly increase over time.

Second quarter 2021 revenue also includes 22.0 million.

Related to tech transfer as part of our strategic manufacturing partnership with Daiichi Sankyo around our Hela, PCL and heck Ciena and 3 technologies through.

And through the rest of the year.

Through the rest of this year the revenue re recognized will taper significantly as the tech transfer activities come to a close.

Additional details on this revenue recognition can be found in our annual and quarterly reports filed with the SEC.

Our total operating expenses for the quarter for $169.8 million, which includes research and development expenses of $113.2 million SG&A expenses of $53.4 million and cost of sales of $3.1 million.

Joshua Higa: development expenses of $132 million.

Joshua Higa: $1 million, SGNA expenses of $53.4 million, and cost of sales of $3. As a reminder, we expect our R&D cost this year to increase versus 2020 as we support three pivotal gene therapy studies, the UX-143, Phase 12, Clinical Study, and OI, the Phase 122 study for our most advanced MRNA program, UXO53 and GSC3, and a number of other preclinical activities as we get ready to advance We also expect SG&A to modestly increase in 2021 as we continue to support the expansion and launches of Krasida, Dojolvi, and Metsev. For the quarter ended June 30, our net loss was $122. or $1.

As a reminder, we expect our R&D cost this year to increase versus 2020, as we support 3 pivotal gene therapy studies. The UX 1 for 3 phase 1.2 clinical study and Hawaii. The phase 1.2 study for our most advanced mrna program <unk>, 3 and GSD III and the number of other preclinical.

Co activities as we get ready to advance the next programs and at the clinic.

We also expect SG&A to modestly increase and 2021 as we continue to support the expansion and launches of Christina <unk> and match Savi.

For the quarter ended June 32021, net loss was $122.4 million or $1.81 per share.

Joshua Higa: per share. This compares to a net income for the same period of 2020 of $25.3 million, or 42 cents per share basic and 41 cents per share diluted. The net loss for the second quarter includes a $31 million decrease in the fair value of investment in equity securities as compared to a $95 million gain in Q20. Net cash used in operations for the six months ended June 30, was $224. compared to $7.8 million for the same period in 2020.

This compares to a net income and the same period of 2020 of $25.3 million or 42 per share basic and <unk> 41 per share diluted.

The net loss for the second quarter 2021 includes a $31 million decrease and the fair value of investments and equity securities as compared to a $95 million gain in Q2 'twenty.

Net cash used in operations for the 6 months ended June 32021 was $224.7 million compared to $7.8 million for the same period and 2020.

Joshua Higa: Net cash used in the first half of 2019 includes the $50 million upfront payment for the closing of the Muriel License and Collaboration Agreement compared to net cash used in the first half of 2020 that included $134.9 million of operating cash received from Daiichi SanQa related to the collaboration and license agreement. We ended the second quarter with approximately $974 million in cash, cash equivalence, and marketable security.

Net cash used in the first half of 'twenty 1.

Includes the $15 million upfront payment for the closing of the morale of license and collaboration agreement compared to net cash used in the first half of 2020 that included $134.9 million of operating cash received from Daiichi sankyo related to collaboration and license agreements.

We ended the second quarter with approximately $974 million and cash cash equivalents and marketable securities.

Unknown Speaker: This puts us in a strong capital position to reach key clinical and commercial milestones as we continue executing our development and commercial strategy. I'll now turn the call over to Josh. Thank you, Josh, and I, too, wish everyone a good afternoon. Today, I will focus my remarks on providing an update on GTX102 being developed with our partner genetics for the treatment of Angelman's syndrome. Angelman's syndrome is a devastating neurogenetic disorder with a broad spectrum of disease manifestations that affect multiple important domains. Last year, we reported surprisingly early positive efficacy data.

That's us and a strong capital position to reach key clinical and commercial milestones as we continue executing our development and commercial strategies I will now turn the call over to Camille.

Thank you, Josh and I too wish everyone a good afternoon.

Today, I will focus my remarks, and providing an update on gtx, 1 and 2 being developed with our partner genetics for the treatment of Angelman syndrome and.

And then syndrome is a devastating narrow genetic disorder with a broad spectrum of disease manifestations that affect multiple important domains.

Last year, we reported surprisingly early positive efficacy data from the first 5 patients treated and the phase 1 and 2 study of genetics excuse me Gtx, 1 O to that.

Unknown Speaker: From the first five patients treated in the phase

Unknown Speaker: in the phase one-2 study of genetics, excuse me, GTX 1022, that indicated substantial improvements in multiple domains in all patients. We also reported that all five patients had a great one or two serious adverse event of lower extremity weakness that has fully resolved. At the first presentation of the SAE, we paused dosing and enrollment in the clinical study. Since then, we have run extensive tests to confirm that this SAE has been fully resolved in all five patients.

And that indicated substantial improvements and multiple domains and all patients.

And he also reported all 5 patients had a grade 1 or 2 serious adverse event of lower extremity weakness that has fully resolved.

The first presentation of the SA E, we paused dosing and enrollment in the clinical study.

Since then we have run extensive tests to confirm that this SAE has been fully resolved and all 5 patients.

Unknown Speaker: Furthermore, we shared extensive clinical and non-clinical data with regulators and have had productive discussions with regulatory agencies, including Health Canada, the Medicines and Health Care Products Regulatory Agency, or MHRA in the UK, and the FDA. Outside of the U.

Furthermore, we share an extensive clinical and non clinical data with regulators and have had productive discussions with regulatory agencies and.

Moving health, Canada, the medicines, and healthcare products regulatory agency or NHRA, and the U K and the F D a outs.

Outside of the U S. Both regulatory agencies have reviewed our data and that's given us the green light to begin treating patients with gtx 1 of them too.

Unknown Speaker: Both regulatory agencies have reviewed our data and given us the green light to begin treating patients with GTX102. They also agreed with our plan to begin dosing in two parallel cohorts with a modified dose titration and administration plan. One cohort will start at 3.3 milligrams for patients under 8 years old, and the other at 5.0 milligrams for patients aged 8 to 17 years. Kandlenberg, or a head-tilted positioning of the body, and an artificial CSF flush should help reduce the local contact time and help the ASO reach the Sisterta Magna as it is diluted and, through circulation, distributed to the brain.

And the agencies agreed with our plan to begin dosing and 2 parallel cohorts with the modified dose titration and administration plan.

1 cohort.

<unk> and <unk> 3 milligrams for patients under 8 years old and the other at 5.0 of milligrams for patients aged 8 to 17 years.

And the ellenburg or of head down and tilted positioning of the body.

And and artificial CSF flush should help reduce the local contact time and help the ASO reached the cisterna Magna as it is diluted and 2 of circulation distributed to the brain.

Unknown Speaker: Careful titration to higher doses may be evaluated on an individual basis after two repeat doses have been first administered to allow the exploration of a dose that is both substantially effective in at least two domains without causing a safety event; dose escalation is capped at 14 milligrams for a single dose. This new dosing plan is within the observed range of clinical and non-clinical activity, but below doses associated with SA In the U.S., We have had a number of productive discussions with the FDA, where we discussed the nature and complete resolution of the SAE, as well as our plan to resume dosing patients in the United States.

Careful titration to higher doses may be evaluated on an individual basis. After 2 repeat doses have been first administered to allow the exploration of the dose that is the substantially affected and at least 2 domains without causing the safety event.

Dose escalation is capped at 14 milligrams for a single dose.

This new dosing plan is within the observe range of clinical and non clinical activity, but the low doses associated with SAE.

And the U S. We have had a number of productive discussions with the FDA, where we discussed the nature and complete resolution of the SAE as well as our plan to resume dosing patients and the United States for.

Unknown Speaker: Based on feedback we received on this amendment, we believe we have agreement with the agency on the dose and method of administration.

Following of type a meeting we submitted a protocol amendment.

Based on feedback we received on this amendment, we believe we have agreement with the agency on the dose and dose administration strategy to treat naive patients the <unk>.

Unknown Speaker: The agency asked that a few specific additional neurological assessments be added to the protocol before we resume dosing in the U. We will make these changes and look forward to resuming the treatment of patients with Angelo syndrome in the U. We and the genetics team have received numerous inquiries from families looking to enroll their children in the study. The data generated will confirm we can safely dose patients with DTX102 and will inform the loading and maintenance dose regimens as we move to the next phase of development. With this update, I will now turn back the call to AML. Thank you. Thank you, Camille.

Agency asked that a few specific additional neurological assessments of the added to the protocol before we resume dosing and the U S.

We will make these changes and look forward to resuming the treatment of patients with Angelman syndrome in the U S.

We and the genetics team have received numerous inquiries for families looking to enroll their children and the study.

The data generated will confirm we can safely dose patients with Gtx 102 and.

1 of them flying and the loading of maintenance dose regimens as they move and the next phase of development.

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

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

Amy: Before we close out, I'll provide a quick reminder of the key upcoming milestones for our ultrigenic. For GTX-O2 and Angelone syndrome, we will dose patients in Canada later this quarter and provide some preliminary data by the end of the year. We also expect to resume the study in the U.

And for Gtx, 102, and Angelman syndrome, we will dose the patient and Canada later this quarter and provide some commodity data by the end of the year.

We also expect to resume the study in the us adapting to the Fda's request.

Amy: Adapt to the FDA's request. For our three pivotal gene therapy studies, DTX 401, DTX 301, and Ux701, all the products have been manufactured and released for use in studies. The sites around the world have been identified, and patient finding efforts are underway as a final operational test that will be completed before we can begin dosing patients. For UX-143 in Osses and Perfecta, we need to reach green with the FDA on a final pivotal study in pediatric and adult patients initiate that study by year end.

For our 3 pivotal gene therapy studies of <unk> for 1 <unk> 3 of 1 and UX 7 of 1.

All of the products have been manufactured and released for Houston studies, the sites around the globe and identified and patient finding efforts are underway. The final operational tasks are completed for full weekend begin dosing patients.

For you, it's 1 for 3 and US jets are perfect.

And you reach green with the FDA and our final pivotal study in pediatric and adult patient initiate that study by year end.

Amy: For UXO53 and GST3, we tend to move our first MRA therapy into the clinic with a phase one-two study. As you can see, we are executing on all fronts with early and late-stage clinical trials in various disease areas in therapeutic modes as well as in commercial. This will set up for multiple important clinical readouts in the coming 12 months as well as pivotal study data from at least four programs over the next couple years. With that said, let's move on to your questions. Operator, please provide the Q&A instructions.

For <unk>, 3 and <unk> 3 we tend to move our first mrna therapy into the clinic with the phase 1.2 study as you can see we were exiting executing on all fronts for the early and late stage clinical trials and the various disease areas and therapeutic modes of wells and commercial and.

And this will set up up for multiple important clinical readouts in the coming 12 months as well as the pivotal study data from at least for program over the next couple of years.

With that let's move on to your questions.

Operator, please provide the Q&A instructions.

Definitely Sir as a reminder to all participants to ask a question you will need to press star 1 on your telephone against that Star 1 on your telephone keypad. However, if your question has been answered and you wish to withdraw from the queue. Please press the pound key.

Operator: Definitely, sir. As a reminder to all participants, to ask a question, you will need

Operator: reminder to all participants: to ask a question, you will need to press star 1 on your telephone against the star 1 on your telephone keypad. However, if your question has been answered and you wish to withdraw from the queue, please press the pound key. Also, please limit yourself to one question with a follow-up. Again, one question with a follow-up. Please stand by while we compile the Kinay Raster.

Also note to limit yourself to 1 question for the follow up again, 1 question with the follow up.

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

Your first question is from Maury Raycroft with Jefferies. Your line is open.

Operator: Your first question is from Morrievee with Jeffre. Your line is open.

Unknown Attendee: Hi, thanks for taking my questions. So I was wondering if you could elaborate on what the additional neurological assessments are that FDA is asking you to use for Angelman. And can you estimate how many patients and how much follow-up you could have to report later this year? Sure.

Hi, Thanks for taking my questions.

So I was wondering if you can elaborate on what the additional neuro assessments are that FDA is asking you to us for Angelman and can your book and how many patients and how much follow up you could have to report later this year.

Sure well.

Amy: Sure, well, we've agreed on what the assessments are, what they want, how we're documenting them, with the training of the person, who it is. They just want, like, a little more of the logistical detail, but these are just really careful neuroexams, we're doing a little bit of electrophysiology, and we'll also do imaging when necessary. They also want us just to be certain of what triggers what kind of action on our part, you know, what you do when you find things.

And we've agreed on what the assessments are the sort of they want and how we're documenting and with the training of the person is who it is.

Like the little more of the logistical detail, but these are just really careful neuro exams and we're doing some deliberate electrophysiology and we'll also have.

Well the imaging when necessary and they also want us just to be certain of what triggers what kind of action on our part you know what you do when you find things.

Amy: So it's a little bit of what I'd call logistical management detail, but I think fundamentally we have the big pieces put together. That's why we're confident we'll get that figured out. It's unfortunate it has taken time to do this, but I think we're finally there.

So it's a little bit what I'd call logistical management detail, but I think fundamentally we have the big pieces put together and it's why we're confident we'll get that figured out.

As unfortunate of taking time to do this but I think we're we're finally there.

Amy: Now, how many patients, it depends a little bit on how many patients get treated in the UK and in Canada. The sites already have patients inquiring. They've gone through their ethics committee, so it's a little bit more of the last logistical steps.

Now on the how many patients and it depends a little bit of how many patients get treated in the U K and in Canada. The.

The sites already have patients requiring they've gone through some of the ethics Committee. So it's a little bit more of the last logistical steps.

Amy: We said before that we'd expect to have a few patients treated with a few doses that we would by the end of the year. The exact number, I think, is hard for us to say, but we'll have some data on a few patients. And we should probably have most of the patients, the first two cohorts, at least receive one dose by the end of the year. So we'll put out whatever we do have, but it will be limited.

We said before we would expect to have a few patients treated through a few doses and that we would by the end of the year the.

<unk> number I think it's hard for us to say, but we will have some data on a few patients and we should probably have most of the patients and the first 2 cohorts at least received 1 dose by the end of the year. So we will put out whatever we do have but it will be limited and it won't be an extensive amount of data, but we do believe it'll give us lease and a sense of are.

Amy: It won't be an extensive amount of data, but we do believe it'll give us a sense of, are we moving in the right direction with the program? Our confidence is that if we give patients three or four doses, that will load them, and that we'll begin seeing these effects, the clinical effects we saw before, without having the adverse event. So we'll start to get a read on that before the end of the year. Great. Thanks for taking my questions.

Are we moving in the right direction with the the program are our confidence is that if we give patients.

For 3 or 4 low doses of load them and then we will begin seeing these effects.

The Couldnt go back and we saw before so without having the adverse event and so we'll get out of start to get a read on that before the end of the year.

Great. Okay. Thanks for taking my questions.

The next question is from <unk> Ahmad with Bank of America. Your line is open.

Operator: The next question is from the Zine.

Operator: Christine Ahmed with Bank of America. Your line is open.

Hi, good afternoon. Thanks, so much for taking my question and.

Unknown Attendee: Hi, good afternoon. Thanks so much for taking the time to answer my questions.

Unknown Attendee: Another one on Angelman, if I may. You made in your prepared remarks the comment that the agency has asked you not to start redoing the previous patients. Is that pending?

And another 1 on <unk>.

The Angelman and if I may.

So you made in your prepared remarks, the comment that the agency has asked us not to start re dosing the previous patients is that pending.

Unknown Attendee: Pending approval for what you're going to do for the new patients that you would add, is that something that would have to be separately discussed?

Approval for what Youre going to do for protocol for the new patients that you would add or is that something that would have to be separately. The Scott.

Unknown Attendee: And then I have a follow-

Amy: Their view right now is that we don't have perfect knowledge of what the reaction was from, and so they'd want us to get patients treated that haven't seen higher doses and just see if it's safe to do, and if it works, and then we could reconsider what to do with retreating patients. But we don't have perfect knowledge of what the mechanism is. What we have said, and what we believe the data we have, suggests it's a local chemical irritation-type effect because there's no cellular response; there's no antibody response.

And then I have a follow up.

Yes, I think there.

The view right now is that we don't have perfect knowledge of what the reaction will from and so they'd want us to get patients treated that haven't seen higher doses and just see if it is safe to do and that works and then we can rediscover what to do with 3 of treating patients, but we don't have perfect knowledge of what the mechanism is what we have said and what we believe the data we have so.

Jess its a local chemical irritation type of effect because theres no sell the response there is no.

Antibody response its really.

Amy: It's really kind of a local contact thing, but we don't have perfect knowledge of the mechanism. So it's mainly about going into naive patients with a lower dose. That way, we know it's nothing about the history of experience. We're now dealing with the low dose alone. We can look at it in a clean way.

Kind of of local contact thing.

So, but we don't have perfect knowledge of the mechanism. So it's mainly about going into naive patients for the lower dose that way, we know nothing about the history of exposure and all dealing with the load us alone and it can look at it and the clean way.

Amy: After that, we will certainly have to get back to retreating the same patients we saw before, but we don't think this changes the timeline of what we do. I think we can get the data we need. It just really is tough for those patients who we're so excited about and want to get retreated. For them to have to wait more time is disappointing for them, but it won't affect the overall program.

After that we will certainly have to get package retreating the same patients we saw before but we don't think this change of the overall <unk>.

<unk> and what we do I think we can get the day that we need and just really is tough for those patients who are so excited and wanted to get retreated for.

And then they have to wait more time is disappointing for them, but it won't affect the overall program, but we do feel for them and we're going to work and getting them treated as we can.

Amy: But we do feel for them, and we're going to work to get them treated as soon as we can. Okay, and then, as a follow-up question, is it safe to say that the FDA is asking

Okay, and then the as a follow up is it safe to say that the the at the FDA is asking for us.

Amy: The FDA is asking for additional information relative to what the UK and Canada asked for. If that's the case, what's prompting that? Well, the actual math.

Additional information relative to what the U K and Canada asks for and if that's the case, what's prompting that.

Well the actual method, we're using and Canada and U K regarding evaluations and safety monitoring is actually the same.

Amy: Well, the actual method we're using in Canada and the UK regarding evaluations and safety monitoring is actually the same. It's the same.

It's the same.

Amy: It's a question of how much detail we provide them. Do we have a checklist form? Is there some other, let's say, operational structure and verification of training, et cetera? They sort of want this more detailed rigor around the same things that we're doing there and doing here. So it's not like they're making us do extra things, really. It's really just the same safety and assessment. I think they're just being very conservative, and they want great assurance that we're going to be careful about what we do.

The question of how much detail do we provide them do we have a checklist for them is there some other let's say operational structure and.

Verification of training et cetera, they sort of want this.

For detailed rigor around the same things that we're doing there and doing here and so it's not like they're making us 2 extra things really it's really the same safety assessments. So.

And I think they're just being very conservative and they want great assurance that we're going to be careful about what we do but of course, we will but I think you can be careful by having really great neurologists who are the sites.

Amy: But of course, we will, but I think you can be careful by having really great neurologists who are on the sites to take care of patients carefully. And then the question is how much documentation makes that better or not. And you can do it. If you have great people, they'll do a good job.

To take care of patients carefully and then the question is how much documentation makes us better or not and.

I think you can do it if you have great people they'll do the job.

So that's the difference.

Thank you.

Your next question is from Gena Wang with Barclays. Your line is open.

Operator: Your next question is from Jenna Wong with Barton.

Operator: while with Barclay's Yelan is open.

Unknown Attendee: Thank you. I have one question regarding Andrew Mann's clinical endpoint. Some doctor feedback suggests CGI has some limitations and relies too much on parents' feedback. What other measurement would you include for the phase 1-2, such as Bayley's or Rhineland? That's what doctors recommend it. And then quickly, another question regarding B&D. Just wondering, are you on track for the R&D filing in the second half this year?

Thank you.

1 question regarding on your main clinical endpoint of some doctor feedback suggests CGI of some limitations on the line too much on parents the box.

Although much of them.

And would include for the phase 1.2 such as babies all volume.

Dalton.

And the mandate and the.

And quickly another question regarding BMP just wondering.

For the R&D filings and hospice.

Unknown Attendee: Did you say DMD?

Did you say D M D.

Unknown Attendee: Yeah, the MDG therapy. All right, well, we'll follow up with that.

Yes, DNV GL, alright, well will follow up of that alright, so on the CGI or of the patient feedback right.

Amy: All right, so on the CGI or the patient feedback story, whatever people are telling them, they're not quite giving the complete story because our evaluations in the trial that Gen X has been doing involved, well, there's a caregiver part, but there are also psychologists who administer tests like the Bayleaf, which were administered by people. And then we have other ones that the investigator measures and does themselves by physically watching the patient do things, not dependent on the patient.

Whatever view of Italian and they're not quite give you the complete story, because our valuations and the trial that you and I've been doing involved well theres. The caregiver part, but there's also psychologists administer test like the Bally were administered by people and.

And then we have all of the ones that the investigator measures and does themselves by physically watching the patient do things not dependent on the patient. So we have really 3 different parties reporting the data and the day that we've already shown you alright, that's all complementary and supportive and addition of that we have objective measures like the Delta power.

Amy: So we really have three different parties reporting the data in the data we've already shown you, all right? It's all complementary and supportive. In addition to that, we have objective measures like the Delta Power, EEG measures, right, or the actomyo, which shows other things. So there's a number of different things that I would say are independent. CGI from the physician, by the way, depends also on what he sees the patient do. But I appreciate their point.

EEG measures right or the act of mile which showed other thing. So there is a number of different things and I would say our independent <unk>.

CGI from the physician by the way it depends also and what he sees the patient to but I appreciate their point I think.

Amy: I think we would want to make sure, and this is why we read out data on these multiple methods, to make sure we have confirmation by independent observers and not be swayed by just the family's view. Now, I know for a fact that our PI at Chicago saw videos of the patients doing things that the parents had said they had done. So they actually were shooting videos of their kids because they were so excited about them speaking words and other things.

We would want to make sure and this is why we read out data on these multiple methods to make sure we have confirmation by independent observers and not be swayed by just the families for Ya.

Also for debt.

Pi at Chicago.

Videos of the patient is doing things that the parents had said they had done so they actually were shooting videos of their kids because they're so excited about the speaking words and other things so <unk>.

Amy: So she also saw video evidence of what they were doing rather than just a patient report, just to be clear, like objective video evidence of things. So we're confident that the things we're seeing are real and are meaningful. Now, let's talk about Duchenne musket dystrophy.

She also saw video evidence of what they were doing rather than just the patient report just to be clear like objective video evidence of things so.

We're confident that the things, we're seeing are real and are meaningful and let's.

Talk about Duchenne muscular dystrophy.

Amy: What we said was we're going to update the street about where we're at on the program. We're not filing ND by this year. But we never said that.

What we said is over and update the street about where we're at on the program, we're not filing and EBIT. This year. We've never said that we said this year is we're focused on creating a large scale commercial manufacturing system and using our hela system.

Amy: What we said this year is that we're focused on creating a large-scale commercial manufacturing system using our Heila system, and that we would put out information about that production system. It's going very well. Our expectation is to be able to put out data on a large-scale methodology using our Heila 3.0 technology later in the year on Dishan and update you on our non-year clinical program. At that point in time, we would potentially lay out the timeline for an I&D, but it's not the end of this year. Okay, thank you. The next question is from:

And that we would put out information about that production system, it's going very well our expectation is to be able to put out data on a large scale.

Methodologies and our heels of 3 point out of technology later in the year on Duchenne and update you on our non clinical program at that point and time, we would lay out potentially the timeline too and <unk>, but it's not at the end of this year.

Okay. Thank you.

The next question is from Yaron Werber with Cowen Your line is open.

Operator: We are in Werber with Cowan Yelan. Hi, this is Brendan, for your own.

Hi, This is brendon on for your own congrats on all of the progress thanks for taking the questions.

Operator: Congratulations on the progress. Thanks for taking the questions. Just a quick one from us, you know; I guess to keep on the same line in Angelman.

A quick 1 from us.

I guess to keep on the same line of and Angelman.

Unknown Attendee: I was kind of just hoping to see if you could maybe give us a little bit more color on the timing for the UK study. I know you said it seems like Canada's pretty close to the first doses. Just wanted to see what's left to maybe get the drug and some patients in the UK and if we might get any of those in the urine data. And then also wanted to see if you mentioned that you set it up on a dosing scheme administration with FDA. Wanted to kind of see if you could tell us if it's the same structure you're using in the UK in Canada or if you're thinking about a different design for that. Thanks.

Kind of just hoping to see if you could maybe give us a little bit more color on the timing for the UK study I know you said it seems like Canada us pretty close to the first doses.

Just wanted to see whats left and maybe getting drug and some patients and the U K and if we might get any of those and the year and data.

And then just wanted to see also if you mentioned that you've set it on the dosing scheme and administration with FDA wanted to kind of see if you can tell us if its the same structure and you're using and the UK and Canada or if youre thinking about the different design for that thanks.

Amy: Okay. So the UK is on track. I mean, it could be the UK or Canada in terms of treating viruses within weeks of each other, so it won't be that much different. We would expect to have some UK patients treated. There's a great deal of enthusiasm from the UK patient community to get enrolled. So once the site's open, we expect them to be able to enroll.

Okay.

So the U K is.

On track I mean, it could be.

U K or Canada in terms of treats the purposes within weeks of each other so it won't be that much different and we would expect to have some U K patients treated theres a great deal of enthusiasm from the UK patient community getting enrolled.

Once the sites open and we expect them to be able to enroll and remember that study.

Amy: Remember that study, we'll have two patients below 2.5-8 first treated, and then a couple of, and then the additional patients will get treated. All right, till there's six and six treated. So we'd expect some UK patients then, but now you're asking about the U.S. The U.S. The U. We'll also have monthly dosing and will have a different dose, but the methodology will be simpler in the U. In fact, not identical to what the U.

We'll have 2 patients below 2.8 first.

And then a couple of US and then the then the additional patients will get treated.

Alright till the 6 and 6 treated.

So that's we would expect some UK patients and now.

And now you're asking about the U S Protocol U S protocol will also have monthly dosing and will have different dose.

But.

The methodology will be simpler and the U K and the U S and fact, not identical to what the U K and Kennedy is doing because of the FDA has made specific request, we have understanding with them about the dosing administration strategy that we're going to use in the us.

Amy: The U.S. Because the FDA has made specific requests. We have an understanding with them about the dose and administration strategy that we're going to use in the U.S. But it is a little bit different. It is monthly dosing. Similarly, but the method so far will be a little bit different based on FDA's input.

But it is a little bit different it is monthly dosing.

Similarly, but the method so for will be a little bit different based on fda's input.

Okay, great. Thank you.

Operator: Your next question is from June Lee with Truist.

Your next question is from Joon Lee with Truest Securities. Your line is open.

Operator: Securities, you're Hi. Thanks for taking our

Alright.

Unknown Attendee: Thanks for taking our questions and for the update.

Thanks for taking our questions and for the.

The updates.

Unknown Attendee: I have a question on Ux-053 for GSC3. We're interested to hear your views on the use of Modifold.

And I have a question on use of <unk> III for GSD III.

We're interested to hear your views on the use of modified versus unmodified mrna given the precedent set by Madonna buy on tech and care of Vac curious of the signals some potential headwinds for off by 3 given our tourists uses the unmodified mrna and such.

Amy: versus unmodified MRNA, given the precedent set by Moderna, by OnTech, and by Kurevak. You know, curious if this signals some potential headwind for 053, given Arturis uses the unmodified mRNA, and some KOL seems to think that Euridine might have contributed to weak data for Kurevac. And they also point out double-stranded RNA as a potential trigger in aid immunity, and so curious what you're using on that, and sort of what kind of biomarkers are you hoping to collect from this initial data on sewage, any concerns there? Thank you. Yes, we think the issue of

Kols seemed the teens that European might have contributed to the week data for share it back and and they also pointed out to double stranded RNA is a potential trigger.

Innate immunity and and so curious what your views on that.

And sort of what kind of Biomarkers are you hoping to collect from the initial data 2 of sewage and any concerns there. Thank you.

Yes, we think the the issue of the innate immunity stimulation of mrna is very important and we actually do.

Amy: Yes, we think the issue of the innate immunity stimulation of MRI is very important, and we actually..., do several things to design. We design the MRI very carefully to assure that they don't induce an innate immunity response, and we actually use peripheral blood monosite cells for patients to actually test our MRNAs to determine they're not having significant amounts of double-stranded in how we purify and prepare them. We have used modified unnecletes. We're using MRNs, so we have to make sure that they're translated efficiently.

Several things to design, we design the MRI is very carefully to assure that they don't induce.

Innate immunity response, and we asked us for.

For the blood monocytes white cells for patients to actually test our mrna is the determined there not having significant amounts of the double stranded and and how we purify and prepare them we have us modified.

Nucleotides, we're using mrna so you'd have to make sure that theyre translated efficiently.

Amy: We haven't disclosed all the details of that, but we know our MRNA is not stimulating human white cells, which we think gives us a handle on that particular issue, and we know the expression is substantial in terms of how much enzyme can be made from the MRNA product. So the old issues with regard to the COVID vaccines, I think, are more complex than just the RNAs, frankly. I think there are a lot of other aspects, like the L&P themselves, and the lipids being used. Those are factors that matter.

We haven't disclosed all of the details of that but.

We know our mrna is not stimulating.

We stimulate and human why itself, which we think us gives us a handle on that particular issue and we know the expression is.

Substantial in terms of how much and then can be made from the mrna product.

So the whole issue with regard to the the Covid vaccines I think are more complex and just see and Rnas.

And frankly so.

I think theres a lot of other aspects like the LNP themselves, which can't lipids being used et cetera, those are factors that matter.

Amy: The Kenneclipit we're using is a novel one that curst developed that is metabolizable and cleared, 99% cleared within a couple weeks from the body, unlike some of the other lipids. So it's a very appropriate one.

The kind of clip and we're using.

As the novel 1.

The current developed debt is metabolized.

And cleared 99% cleared within a couple of weeks for the body. Unlike some of the other lipids. So its a very appropriate 1 and releases early and the Swiss gives us better expression.

Amy: It releases early, and this is what gives us better expression. So we think the L&P is a factor, too, and how this works. But RMNA quality We do a lot of work in optimizing how we prepare, purify, and use modified nucleotides as needed.

So we think the LNP the factor too and how this works, but the M&A quality, we do a lot of work and optimizing how we pair of prepare purify and use of modify nucleotides if needed.

Thank you.

Your next question is from Saudi and the Richter with Goldman Sachs. Your line is open.

Operator: Your next question is from Saldine Richter with Goldman Sachs. Your line is open.

Operator: Hi, good afternoon, and thank you for taking your question. This is Elizabeth on behalf of Salveen.

Hi, good afternoon, and thank you for taking your question and this is Elizabeth <unk> for solving the question on the Engelman Angelman program. So I know previously you sort of the sky expanding the program to include other genetic types outside at the analyst day would be our installation base patients just wondering how this would work in terms of the trials and <unk>.

Unknown Attendee: I have a question on the Angleman's program. So I know previously you've sort of discussed expanding the program to include other genetic types outside of the most severe deletion-based patients. Just wondering how this would work in terms of, you know, the trials in progress or if it's more of a future consideration. We definitely think the other genetic types deserve to be retreated; we think the ASO, if it works, and the deletion type, it will work in the other types based on the mechanistic understanding. Our plan right now is to focus on the 70th percentile of the patients who have deletions for the program we're conducting.

Sorry, if it's more of the future consideration.

But we definitely think the other genetic types of observed retreated and we think the ESO if it works and the deletion type of will work and the other types based on the mechanistic understanding of.

Our plan right now is the folks on the 7% of patients of deletions for the program. We are conducting however, we would probably put in place. The second study to look at other genetic types.

Amy: However, we would probably put in place a second study to look at other genetic types. The reason to focus the main Pivot study on the deletion type is that they are more severe. Therefore, any improvement you see in language and communication, which is one of the main things that patients are most interested in, would be clearer if we have a mixture of patients who have varying degrees of communication skills, and words. It would just create difficulty in a pivotal randomized study.

The reason to focus the main pivotal study on the deletion type of it's because they are more severe and therefore any improvement you see and language and <unk>.

<unk>, which is 1 of the main things of that patients who are most interested and would be clear. If we have a mixture of patients who have varying degrees of communication skills and.

And words et cetera, it would just create difficulty and a pivotal randomized study. So we'll focus on those and but we're not going to forget the other types of and put some program in place to deal with the other types as well.

Amy: So, we are not going to forget the other types. We put some programs in place to deal with the other types as well. But creating heterogeneity in the main body of a big study is one of the ways you can create trouble for something that's doing great, so we wouldn't do that.

But creating heterogeneity and the main body of a big study.

As a as.

And as 1 of the ways you can create.

Trouble for something that's doing great. So we wouldn't do that.

Thank you.

Operator: Your next question is from Joseph Schwartz.

Your next question is from Joseph Schwartz with SBB Leerink. Your line is open.

Operator: where SVB Your line is open. Hi, thanks very much. We noticed a couple questions on Chris Vita.

Alright, thanks, very much we noticed a couple of questions on Christina first we noticed that the label was updated in Europe to allow patients to self administer the therapy and we were wondering.

Unknown Attendee: First, we noticed that the label was updated in Europe to allow patients to self-administer therapy, and we were wondering, what impact do you expect this to have, if any, and do you think we could see a similar change take place in the U.S. at any point in the foreseeable future? Thank you, but in the U.S., we actually have temporary authorization from the FDA to allow self-administration, which is going on already because of the pandemic. We haven't submitted to change that at this point.

What impact do you expect this to have.

And do you think we could see of similar change take place in the us at any point in the foreseeable future.

Thank you Jos but in the US right now we actually of temporary authorization from the FDA to allow self administration self administration, which is going on already.

Because of the pandemic.

We haven't submitted the change that at this point, we have done the human factor study the <unk>.

Amy: We have done the human factor study. The drug administration is very similar to what you might do for any other subcutaneous drug. There's nothing very special about the injections or problems. So it certainly could be added.

Ministration is very similar to what you might do for any other subcutaneous drug that's something very special about the injections or problems. So it certainly could be added it has complexity and though and the U S. Because we have to deal with the different systems.

Amy: It has complexity, though, in the U.S. because we have to deal with the different systems, whether it becomes a medical product, a hospital product, or a home product, or not a Part B product. So we have some complexities in the US at this point in time, but patients are doing self-management, and I think in the long run, we would certainly move in that direction. We haven't had a big compliance issue, and I think one of the most important things is to know that we support right up front and do, including the cost of the drugs, getting a home nurse that comes to your home and injects you.

And whether it becomes the.

Medical product and household product or a home.

Home product or.

Not a part D product. So we have there's some complexities and the U S. At this point in time, but we are of patients are doing self administration and I think of the long run and we would certainly moving that direction.

We haven't had a big compliance issue and I think 1 of things and the important Joseph day know that we supported right upfront and do include and the cost of the drug getting out of home nurse that comes to your home and inject you. So the 85 plus percent of the patients are getting their of stuff at home already.

Amy: So the 85 plus percent of patients are getting their stuff at home already. So the benefit of self-administration is you don't have someone show up at your house. On the plus side, there's a lot more confidence that you're going to get your injection on time since it's an appointment, but, um, we want to make sure it's as convenient as possible because it is a lifelong treatment, so we'll look at self-management in the long run.

Right. So the the benefit of self illustrations and you don't have some show up at your house.

And on the plus side.

There's a lot more confidence that youre going to get your injection on time since it's an appointment but.

We want to make sure it's and Dominion as possible because it is of lifelong treatment. So we will look at self administration of long run, but so far the human errors.

Amy: But so far, the home nurse is working well, and some of the patients are doing it for now on temporary authorization. That's a helpful color, and then does the need for Brazilian patients to use the legal system to gain access?

Working well and some of the patients are getting are doing it for now on the temporary authorization.

Okay. That's helpful color. Thanks, and then has the need for Brazilians and patients to use the legal system to gain access to Chris of either been holding back.

Unknown Attendee: Best at Chris Vett, has been holding back adoption there to an appreciable degree.

Adoption, there and 2 and appreciable degree can you quantify the impact you'd expect to see on Chris', Vito and Brazil sales from potential and visa approval.

Unknown Attendee: Should both agree? Can you quantify the impact you'd expect to see on Chris Vresil?

Unknown Attendee: Chris Vita Brazil sales from potential end visa approval?

Unknown Attendee: You know, we have the approval, and we are getting injunctions and Ministry of Health orders. That's the lumpy ordering pattern we're seeing, but it is, we are getting orders, and that is growing over time.

Well you know.

And we have the approval and we are getting we are getting injunctions and ministry of health orders. That's the lumpy ordering pattern, we're seeing but it is there we are getting orders and that is growing over time, what we're talking about today is getting formal approval.

Amy: What we were talking about today is getting formal approval of the organization within Brazil that actually determines government reimbursement. With that, it would help get more regular reimbursement for Brazil. So that is near the final stages. And once that's completed, we'd expect that would help boost Brazil further, so we wouldn't have as much of the logistical challenges of what you're doing with the injunction approach.

Of the organization within Brazil that actually determines the government reimbursement with that it would help get more regular reimbursement for Brazil for that that is near the final stages and once that's completed we would expect that would help boost the Brazil further.

So we wouldn't have as much of the logistical challenges of what Youre doing with the injunction approach does that answer your question.

Amy: Is that answering your question? Yeah, I was just wondering if there is any way to quantify how much the current system's been holding back sales or, you know, how much you could get a boost from. I don't know, yeah, Eric, do you think there's so much color on that? I don't have any sense for what that would be. I know we have a lot of patients want to get on drugs, so it's definitely holding back something. Eric, do you have any sense for how many patients are in demand, I mean, a rough sense, and how many actually go through the process?

Yeah. That's helpful. I was just wondering is there any way to quantify how much.

The current.

Our system has been holding back sales.

Or how much could you get a boost from I don't know yeah. Let me Eric do you think theres. So many color on that I don't have any sense for what that would be.

I know, we have a lot of patient and wanted to get on drug. So it's definitely the holding back something Eric you of any sense for how many patients are and demand I mean the rough.

And how many actually and navigated the net and the process.

Amy: We've done a good job of identifying patients, and many of those patients have sought injunctions, and as stated, many have received injunctions and are receiving reimbursed therapy. I would say, to the magnitude of about two to threefold patients that have been identified and are seeking reimbursement versus those that have received an injunction. So there's some upside once we receive formal reimbursement. And one thing I do want to point out, just to piggyback on what Amos stated, is that in the first quarter, we did receive a positive opinion supporting reimbursement in Brazil. We're just working through that final stage, which is establishing clinical guidelines, which is the next step in the approval process. And we expect to complete that sometime in the new year. Thank you.

Yes.

We've done it we've done a good job of identifying patients and many of those patients have saw us injunctions and as stated many of them have received the injunctions and are receiving reimbursed therapy I would say.

So the magnitude of about 2 to threefold.

Patients debt.

Have been identified and are seeking reimbursement versus that have received the injunction and so.

There's there's some upside once we were seeing.

The formal reimbursement and 1 thing I do want to point out just to piggyback on what the name of state is debt and the first quarter. We did receive a positive opinion supporting reimbursement in.

In Brazil, we're just working through that final stage, which is establishing clinical guidelines, which is the the next step in there and the approval process and we expect to complete that some time.

And the new year.

Alright, Thanks, again, yes very good.

Operator: Thanks again. Very good.

Yes.

Operator: Your next question is from Corey Kasimov.

Your next question is from Corey casting of with JP Morgan Your line is open.

Operator: Jeper Morgan, your line is open. Hey, good afternoon, thanks for taking the question. On Angelman, had the FDA conveyed this concern before about retreatment?

Hey, good afternoon, guys. Thanks for taking the question.

And on Angelman and has had the FDA conveyed this concern before about re treatment because it seemed like that was the plan for the go forward strategy and the us until very recently I guess, just wondering if there's something new that triggered this change and direction.

Unknown Attendee: because it seemed like that was the plan for the go-forward strategy in the U. until very recently. I guess I'm just wondering if there's something new that triggered this changing

Unknown Attendee: triggered this changing direction. Well, we had our type A meeting with them, and this work It was pretty clear that they were just concerned the patients that had a reaction might be more sensitized to have it again, and therefore they'd have trouble determining that the safety would have been different had they had a patient who never had the reaction as opposed to one that did. Does that make sense?

Well, we had our type a meeting with them.

And that's where.

It was pretty clear that day.

They were just concerned of the patients the hatter reaction might be more sensitized tablet again, and therefore, they would have trouble of determining of the safety would have been different had to have a patient who never had the reaction as opposed to 1 that did that makes sense. So.

Amy: So, in terms of understanding what's going on, they felt it's safer to start with a Knave patient, and they want us to hold back on that. There's no new data that help or change their mind. We have no new data regarding things that might cause them to have a more severe reaction; we think, based on everything we have, they don't have anything that we think would occur that way. We can't prove the mechanism exactly, right?

In terms of understanding what's going on and they felt the safer to start with the nave patients and they want us to hold back on that.

There's no new data that help.

Change their mind.

We have no new data.

Regarding.

Things that might cause them to have a more severe reaction we think.

Based on everything we have that they don't have something that we think would prefer that way, but we.

We can't prove the mechanism exactly right and so without that proof the.

Amy: And so without that proof, the agency wants to play it safe with regard to who they exposed in the beginning. That's the story. There isn't anything new that came out, for example, that would have made that new change. It's just something they finally disclosed to us at the type A meeting. Okay, makes sense. And then I just wanted to try to clear up the dosing you're expecting to use in the U.S. You said it's going to be different.

The agency wants to play it safe with regard to.

And who the exposed in the beginning.

So that's the story there isn't anything new that came out for example that would have made that new change.

Something they finally disclose to us at the type a meeting.

Okay. It makes sense and then I just wanted to try to clear up the dosing and you're expecting to us in the US you said, it's going to be different.

Unknown Attendee: than Canada and the UK. Is it that you're going to start with lower doses and work your way up, or would it be higher doses here given that you've treated some patients? Now, we're going

And then than Canada, and the U K is it that youre going to start with lower doses and work your way up or or would it be higher doses here given the treated some patients.

No, we're going to start a little bit lower.

Amy: Now, we're going to start a little bit lower; we think that it's still in a range that will load the patient sufficiently over four doses to get a treatment effect, but I think the FDA wants to be more cautious. And so, you know, we went along with what you have to do to get going. No, okay. Thanks a lot; I appreciate it.

We think that.

It's still and a range that will load the patients sufficiently over for doses to get at the treatment effect.

But I think the FDA wants to be more cautious.

And so you know.

We went we went along with what you have to do to get going.

Absolutely okay. Thanks, a lot of and I appreciate it.

Operator: Your next question is from Hugo Nucer with Siri. Your line is open.

Your next question is from the Eagle Mitchum of it with Citi. Your line is open.

Operator: Hi, this is Carly on Free Agall. Thanks for taking our questions. We had a couple on Wilson disease.

Hi, This is carly on for Yigal. Thanks for taking the question we had a couple of line of Wilson disease.

Unknown Attendee: As far as the target patient profile for the phase one, three trial, will you be focused on recruiting patients with established disease or

And as far as the target patient profile for the phase 3 trial will you be focused on recruiting patients with established disease or is the focus on treating newly diagnosed patients.

Unknown Attendee: is the focus on treating newly diagnosed patients. Just curious if there could be an advantage in terms of the magnitude of benefit with UX-701 if you're able to capture patients earlier versus later in their course of the disease. And then, secondly, what is your expectation at

Curious if you think there could be an advantage in terms of the magnitude of benefit with <unk> line of Youre able to capture patients earlier versus later and that of course of therapy.

And then secondly, what is your expectation at this point for when we could potentially see some initial data for this program and from the dose escalation part of the study. Thank you.

Unknown Attendee: point at which we could potentially see some initial data for this program from the dose escalation part of the study. Thank you.

Amy: Yes, thank you; the patients will be patients who have or established patients who've already had a key later on. The problem with doing naive is it would be very few patients, and it would greatly slow enrollment. It would take a long time.

Yes. Thank you so.

The patients will be patients who.

Our established patients who've already had key later honestly and are key later the <unk>.

Doing naive as it would be very few patients and it was greatly slow enrollment would take a long time.

Amy: I don't disagree with the thesis that treating patients early before they've changed would allow a cleaner result. But we do believe that since the keylater removes copper by bringing it into the urine, and what we're doing will bring copper into the bile, that we'll be able to look at urinary copper and show that the copper is no longer ending up in the urine, oozing out of the liver or being chelated; it's going to be routed into the bile, right? Does that make sense?

I don't disagree with the thesis that treating patients early before the.

Change would allow us cleaner result, but we do believe that since the key layers removed copper by bringing it into the urine and what we're doing will bring copper into the bile that we'll be able to look at urinary copper and show that the copper is no longer ending up in the air and oozing out of the liberal of being <unk>, it's going to be.

Routed into the bile right does that makes sense, so even though they're on drug we can determine of the copper pathway is changing and the body.

Amy: So even though they're on the drug, we can determine if the copper pathway is changing in the body and if seruloplasin's gone up or down. So it won't really matter if they aren't established or not.

And if the rule of plasma has gone up so it won't really matter if they aren't established and that we can see the difference happening and the truth is there's so many more patients of an established therapy be it takes a long time to do it the other way in the long run, though using 90 patients I think would give you. The cleaner result, and I think taking patients earlier and their course might change.

Amy: We can see the difference happening. And the truth is, if so many more patients were on established therapy, it would take us a long time to do it the other way. In the long run, though, using naive patients, I think would give you a cleaner result. I think taking patients earlier in their course might change people's views of what's happening. Everyone believes it's just excess copper, but it's also possible that it's copper not being properly distributed as well.

People's view of what's happening everyone believes it's just the excess copper, but it's also possible that is copper and not being properly distributed as well that's part of the symptomatic problems that youre seeing and Wilson and.

Operator: That's part of the symptomatic problems that you're seeing in Wilson, and we think gene therapy can fix both. So that's our focus based on the ability to conduct the study and the way we can measure it. Now, with regard to wind data, we expect to be able to get the patients enrolled in the dosing relatively quickly. I can't say specifically when that data will come out, but we will put it out. It could be by the end of 2022, but I'm not 100% certain.

And we think the gene therapy and fixed both so.

And that's our focus based on the ability to conduct the study and the way, we can measure them and with regard to when data.

We expect to be able to get the patients enrolled and the dosing relatively quickly.

I can't say, specifically when that data will come out, but we will put out the it could be by the end of 2022.

But I'm, not and arms and certain it depends a little bit on kind.

Operator: It depends a little bit on the Delta virus sites, execution, but we're up and running with products ready, sites are getting set up, And we have, I think, a very, convenient protocol that will be easy on patients, so I think it will help make recruiting easy. Okay, that's very helpful. Thank you so much. Your next question is from Laura Tico with Redbush. Your line is open.

The Delta virus sites execution, but we're up and running products ready sites are getting setup.

And we have of I think of very.

Convenient protocol that will be easy on patients. So I think it will help.

Net recruiting easier.

Okay, Great. That's very helpful. Thank you so much.

Your next question is from Laura Chico with Wedbush. Your line is open.

Operator: Thanks very much for taking the time to answer my question. Just on Angelman, you've commented in the past on the potential potency differences between GTX 102 and the Roche program. Then there's also another program starting from Biogen. I'm wondering if we could just take a step back, and what are your thoughts about the key elements of differentiation in a clinical setting for all these ASO targeted strategies? Are there logical points at which two agents might differ?

Thanks, very much for taking the question just on Angelman.

And you've commented in the past and the potential potency differences between Gtx 1 of 2 and the Roche program and Theres also another program starting from Biogen and I'm wondering if we could just take a step back and how do you think about the key elements of differentiation in a clinical setting for all of these assets targeted strategy strategies.

Are there logical points in which 2 agents might differ.

Unknown Attendee: If this is still kind of evolving, what kind of aspects should we be focusing on as the clinical trials get underway here? And then just one quick follow-up. With respect to the dosing in Angelman patients in the UK and Canada, I think in the past, you've spoken about getting them through the titration, getting up to a steady state level. It isn't clear to me how many patients are actually going to be at that range, especially if we're going to be needing more like three or four doses. I guess I'm just trying to understand how the response data might differ this time around versus the prior experience. Thanks.

And if this is still kind of evolving I guess, what kind of aspect should we be focusing on is the the clinical trials get underway here and then just 1 quick follow up with respect to the the.

Dosing and Angelman patients and the U K and Canada I think in the past you've spoken about.

Getting them through the titration and getting up to a steady state level.

It isn't clear to me how many patients are actually going to be at that range and especially if we're going to be needing more of like 3 or 4 doses I guess I'm just trying to understand how you think the response data might differ this time around versus the prior experience. Thanks.

Okay.

Amy: So on the competition. We know the mechanism for this all go is special. The patented region is different. It's at the 5 prime end.

On.

The competition.

And we know the mechanism for this all go is special and the reason is the patented region is different it's at the pipeline and then.

Amy: I think Dr. Dindo is shown that it is far more potent than antisense all goes from other parts of the message in terms of knocking down the production of the mess, the antisense message, and the level of induction. I think each ASO could have varying levels of potency and penetration, but I think you want to have high potency across the brain, and you want to bring the MRNA down, I mean, the S, the anti-s RNA down far enough to get significant induction of the message.

I think doctor didn't know as shown that is far more potent than antisense oligos from other parts of the message in terms of knocking down the production of the mess antisense message and the level of induction I think each asl could have varying levels of potency and penetration.

But I think you want to have high potency across the brain and you want to bring the mrna down I mean the F.

The antisense RNA down far enough to get significant induction of the message and we've shown that we can do that with a relatively small amount of drug and debt.

Amy: And we've shown that we can do that with a relatively small amount of drug and that That effect goes across the whole brain to all regions. I think the difficulty will be how well the oligals are distributed and how well they are able to knock down. And because all ASOs have toxicity, it's very common. You've seen them on a lot of programs.

And that effect goes across the whole brain for all regions. So I think the difficulty will be how well, they're all the all of the goals of distributing.

And how well are they able to knock down.

And because of all of <unk> have toxicities, and it's pretty common you've seen them a lot of programs the drugs that have a lot of potential of.

Amy: They're drugs that have a lot of potential, and challenges the potency will then become a question of therapeutic window. I do believe if we're able to successfully dose in the single-digit range, you know, single digit, low double digit, and achieve the efficacy we saw, that will greatly reduce the possibility of having systemic ASO side effects that you sometimes see or other neurological effects. So, certainly that's our expectation, on the type of dosing and titration story. In the first set of patients, we're treating two in each group, and then we're going to add four and four, so it'll be 12 patients total, right?

The challenges the potency will then becoming the <unk>.

And of therapeutic window.

I do believe if we're able to successfully dose and the single digit range.

No single digit low double digit and achieve the efficacy we saw that will.

Greatly reduce the possibility of having systemic ASO side effects that you, sometimes see or other neurological effects. So.

Certainly that's our expectation.

And so.

On the tight dosing and titration story.

And the first set of patients we're treating 2 and each group and then we're gonna add.

For and for Us so it'll be swaths of patients total right. We'll have 12 patients and from the 12, we'll get a read on where do they seem to be getting and the efficacy and what dose or the at once we get that information, we're going to try to look at it and try to make sense of how is the optimum way the dose going forward.

Amy: We'll have 12 patients, and from the 12, we'll get a read on where they seem to be getting the efficacy and what dose they are at. Once we get that information, we're going to try to look at it and try to make sense of how it's often the dose going forward. But we've said before, once, if we see safety and we get good efficacy, we'll take that information and translate it into a dose that we will use in an expanded cohort of, say, 30 or 40 patients.

And we've said before once if we see safety and we're getting good efficacy will take that information and translate it into us.

A dose that will use and and expanded cohort of say 30 or 40 patients those patients would get a starting dose based on the dose achieved during the titration and use that as the starting dose does that help you and the idea that the 30 to 40 would now have a little more standardized dosing regimen alright.

Amy: Those patients would get a starting dose based on the dose achieved during the titration and use that as their starting dose. Does that help you? And the idea is that those 30 to 40 would now have a little more standardized dose.

Amy: That makes sense? It was high-triti-intervention to learn a little bit, and then standardize it in the next group. Got it. Thank you, Amel.

Does that makes sense yeah. It was the highest grade individuals learn a little bit and then standardize it and the next group.

Got it okay. Thank you Emil.

Operator: Your next question is from Degon Howard Steeful. Your line is open. Okay.

Your next question is from dig and how with Stifel. Your line is open.

Operator: Great, good afternoon, thanks for squeezing me in and congrats on all the progress. Maybe one question on Angelman and then a quick one on 401, Amel. So on Angelman, a lot of my questions have been answered, but just curious, on Clinton trials, you have one site in Canada and one site in the UK, but just going back to the variability issue, will you have a centralized reading for the CGI to make sure that there is a confident vote in terms of the CGI benefit, as well as some of the other benefits that are included?

Great. Good afternoon, and thanks for squeezing me in and congrats on all of the progress of maybe 1 question on Angelman and then a quick 1 on 401, Emil So on Angelman and a lot of my questions have been answered, but just curious on <unk> trials, you have 1 site and Canada, 1 side and the U K.

But just going back to the variability issue will you have a centralized reading for the CGI to make sure that there is a.

Confident vote and terms of the CGI benefit as well as some of the other benefits that are included and then on for O..1 I was.

Operator: And then on 401, just curious, given that one of your endpoints measures glucose control using CGMs, I was wondering if the protocol entails any backups in case the CGM starts malfunctioning or any validations for any significant variability that might occur during the study. Thank you.

Just curious given that 1 of your endpoint measures the glucose control using CGM and was wondering if the protocol and tails any backups in case CGM and start small functioning of any validation for any significant variability that might occur during the study. Thank you.

Unknown Attendee: Sure, but there's really no way to do CGI centrally because it's an opinion of the physician there, and not everything they're doing in terms of valuing the patient could be centralized, and turned into a video. We will train the sites on the various endpoints. The CGI, there's a global one, and then there's individual ones for individual domains, which have specific questions that they answer, and we'll try to, we will do our best with our team to train the CGX team to train the sites to be able to do these tests.

Sure so.

And there's really no way to do of CGI centrally because it's the opinion of the physician there and not everything they're doing in terms of the value of the patient could be centralized turned into video.

We will the sites will be trained on the various endpoints the CGI Theres a global 1 and then there's individual ones for individual domains, which of specific questions. The answer and we will try and we'll do our Bachelor of team to train and the C. Jack's team to train the size to be able to do the tests. We also have a number of tests that are not.

Amy: We also have a number of tests that are not CGI, right, that have basic scoring mechanisms and are being administered by professionally trained psychologists, for example, as well as some other objective measures. So we won't be relying on CGI to make all the calls. But I think CGI will give you a gestalt feeling about the P, I think.

CGI right that our debt have basic scoring mechanisms and are being administered by professionally trained psychologist for example, as well as some other objective measures. So we won't be relying on CGI to make all of the calls I think C. J will give you a guess stopped feeling of what the P. I think.

Amy: But as we noted when we presented this data before, you want to look at the other endpoints to show there's an underpinning, right? Because having CGI without any underpinning and the rest of the data would be suspicious, right? That someone's just, you know, wishful thinking, hoping they're better.

But as we noted when we presented this data before you want to look at the other end points to shoulders, and underpinning right is having CGI without any underpinning and the rest of the data would be suspicious right if someone's just.

You know wishful thinking, hoping they're better, but if they're really better there should be something else happening. So we feel confident we can manage the question of the objectivity by using the supporting data.

Amy: If they're really better, there should be something else going on. So we feel confident we can manage the question of objectivity by using the supporting data. Now, with regard to 401, CGM controls, while we will have them continuously monitored, we're actually going to take windows of sample time and do the calculations for how they're doing. So if, for example, they had a probe and the probe fell off and stopped working, we would see the defect. We could take the period of time when they sampled, right, effectively, and calibrated, and so they're going to put them on, calibrate, and measure for a period, and we'll use these sample periods. Does that make sense?

And with regard to 401.

The CGM controls, we want well, we will have them continuously monitored were actually to take windows of the sample time and do the calculations for how they're doing so if for example, they had a probe and the probe fell off and stop working we would see the defect we could take the period of time when they sampled right effectively.

And calibrated and so theyre going to put them on calibrate measure for a period and we'll use the sample periods is that makes sense. Because if you are expected to be able to use all of the day to continuously for months and months right, yes, stuff's going to happened during that period, but we will have periods of assessments that are and intervals of time, we're going to.

Amy: Because if you expect to be able to use all the data continuously for months and months, yes, stuff's going to happen during that period, but we'll have periods of assessment that are in intervals of time. We're going to watch it more carefully, more closely, and we'll take windows of sampling that will be where it is verified as, you know, operating correctly, calibrated correctly, and receiving. So that should help protect us against the kind of digital disaster you're talking about. And we've been thinking about that, too. I would also point out that the devices collect locally, and then they collect in the cloud, too. So it's actually double collected.

Watch it more carefully and more closely and will take windows of sampling that will be where is verified us.

Operating correctly calibrated correctly and and are receiving.

So that should help protect us against the kind of digital disaster Youre talking about.

And we've been thinking about that too.

I would also point out the devices collect locally and then they collect and the cloud too so its actually double collected and.

Amy: If anything, we could actually ship the device and do it. But that doesn't stop a patient from having a probe malfunction or something, right? So you have to include all levels of the problem, not just digitally, but on the physical parts, connect to the patient, which is probably the bigger source of questions. But we've had good experience so far. We're getting a lot of good data from it on the patient, so we feel pretty comfortable. We can get this to work without having a lot of trouble. Very good. Next question.

And we could actually ship the device and do it but that doesn't stop of patients from having a probe malfunction or something right. So you have to include all levels of the problem not just digitally but on the physical parts connect to the patient which are probably the bigger ish source of of questions, but we've had good experience so far.

Getting a lot of good data from it for the patients. So we feel pretty comfortable we can get us to work without having a lot of trouble.

Very good next question.

Operator: Okay, your next question is from Lisa Baker with Evercore.

Okay. Your next question is from Lisa <unk> with Evercore ISI. Your line is open.

Operator: Evercore ISI, your line is open.

Unknown Attendee: Hi, Amel, thanks for taking my question. Just to Claire

Hi, I'm all thanks for taking the question.

Just to clarify so and the U S for <unk>.

Unknown Attendee: So in the U.S., just back to Angelman's,

Unknown Attendee: back to the Angelman program. Even though you're starting lower, can you still escalate up to the 14th? milligram level? We'll start lower and see how we do, and then we'll treat several doses at a lower dose, which, as I said, should still give us enough drug to show an effect. And then, if we've established safety there, we have safety elsewhere; we'll then, you know, apply for the FDA to kind of titrate them.

Back to the Angelman program, even though youre, starting lower can you still escalate up to the team.

The milligram level.

Well, we will start lower and see how we do and then we.

We will treat the several doses and a lower dose, which as I said should still give us enough drug to show an effect and.

And then if we the established safety there and we have safety elsewhere will then apply to the update of the kind of titrate them up.

Unknown Attendee: But we're kind of taking baby steps forward in the U. Get them tested, get some data, and get comfort; whatever happens in the U.S. will not control the future. We will have U.K. and U.S. sites; more than one site doing it, and with all that data together, we'll come up with a plan. I think the agency is being very conservative, fairly typical for them, and we are just working our way to get going, but I don't think it's going to affect anything. It just may. It will delay our ability to titrate those patients, but we will still have enough drug on board to know that it's safe and to know that it is doing something for them.

But we're kind of taking baby steps forward in the us get them tested get some data and get comfort.

But.

Whatever happens in the us will not control of the future, we will have U K and U S sites more than 1 site doing and with all of that day together will come up and come up with the plan I think the agency is being.

Very conservative and it's fairly typical for them and we are just working our way to get going but I don't think it's going to affect anything and it just may.

It will delay our ability to titrate those patients, but we will still have enough drug on board to know that it's safe and to know that it is.

Doing something for them.

Amy: Okay, okay.

Okay I see okay.

Unknown Attendee: Thank you, that's helpful. So there's no, the mast dose is basically not determined.

Thank you that's helpful and.

And so theres no other than the vast doses basically not not determined or is there a.

Unknown Attendee: not determined or is there a, you kind of set it at 14 for the other. For XUS, we agreed at 14, based on the other authorities. 14 is a max. But in the U.

And you can kind of set us up for it and for the other.

For ex U S. We agreed in 2014 based on the other authorities with 14 of the Max.

But in the US we havent set of Mac because were not tight trading and we're starting at a low dose we're going to repeat that multiple times and the FDA has agreed to that.

Amy: We haven't said a max dose because we're not titrating them. We're starting at a low dose, and we're going to repeat that multiple times, and the FDA has agreed to that. I'll get us started and start getting some data.

So I'll get us started and start getting some data.

Okay.

And then.

Amy: And then last thing is just on your gene therapy programs, GSD1A and OTC.

Well the thing is just on the your gene therapy programs that just you want an OTC.

Unknown Attendee: I know your endpoints are 48 and 64 weeks. Do you need a greater safety database than that? I'm just thinking back to Biomerin for filing and kind of longer-term efficacy, or can you really file on that when you reach a primary endpoint sufficient to file? Thanks.

I know your endpoints are 48, and 64 weeks deal do you need the greater safety databases and that and just thinking back the biomarin or.

And to file or and the kind of longer term efficacy or can you really file on that.

When you when you reach the primary endpoint of sufficient to file for now thanks.

Amy: Yes, it's a good question. I think the key thing here is that we will have 12 patients from the earlier cohort in both programs that have been exposed, and that will give us some sense of durability. Now, so far, it looks durable.

Yes, it's a good question I think the key thing here is that we will have 12 patients.

From the earlier cohorts.

And both programs that have been exposed that will give us some sense of durability.

And so far it's look durable I think the challenge of Biomarin is they had some decline in activity and the FDA was trying to understand the direction.

Amy: I think the challenge with Byrida, they had some declining activity, and the FDA was trying to understand the direction. Our disease is much smaller, remember, than hemophilia. Remember, hemophilia has 100,000 patients in it. Our diseases have 8,000 to 10,000 patients, one-tenth of that. So the size of our trial compared to the population size is actually substantially larger, right? So we're taking a bigger sample. In addition to the 50 patient trial and the 12 patient one, phase 1, 2, you know, it's very likely we might add some additional patients that we would treat who, for example, are at different ages or other situations that we would add to the package.

Our disease are much smaller number than hemophilia, a hemophilia has 100000 patients and it are diseases have the 8 to 10000 patients 110th.

For the size of our trial compared to the population size and actually substantially more right. So we're taking a bigger sample and addition of the 50 patient trial and the 12 patient 1.

Phase 1.2.

Very likely we might add some additional patients that we treat the for example of different ages or other situations that we would add to the package, but right.

Amy: But right now, we believe these numbers are fine, and frankly, we have not had any regulatory theory debate the size of the studies with us. And remember, the 50 randomized, the other 25 will get treated too, right? So they'll all cross over, so you'll have 50 patients treated. 62 patients treated, it's pretty normal safety set for rare disease products. It's not an unusual one. For gene therapy, I think it's good

Right now we believe these numbers are fine and frankly, we have not had.

And the regulatory debate the size of the studies with us.

And remember the 50 randomize the other 25 will get treated too right. So the all crossovers and you'll have shipped the patients treated.

No.

The 62 patients treated it's pretty normal set of <unk>.

<unk> set for rare disease products.

The unusual 1 and for.

The gene therapy I think it's good.

Okay.

Thanks Emel.

Thanks Lisa.

Operator: Your next question is from Jeff Huang with

Your next question is from Jeff hung with Morgan Stanley.

Operator: is from just hanging out with Morgan Stanley. Thanks for taking the question. Most of mine have already asked.

And thanks for taking the question of most of most of my word yes. So you recently indicated that patient identification for Christina had come back to pre pandemic levels and.

Unknown Attendee: So you recently indicated that patient identification for Chris Bida had come back to pre-pandemic levels. Any additional update on that level since then, particularly given the Delta variant and recent increase in COVID? Thanks. Yeah, it seems to be going pretty well. I think it's just people have adapted to the new world, and so we're still doing a lot of virtual work, and people are responding and getting things done. So I don't know that we've seen anything from Delta, and I'm not sure if Eric or Camille have something to say about patient ID and Delta at this point.

Any additional update on that level since then, particularly given the delta Varian and recent increase in Covid.

Yes, it seems to be going still pretty well I think it's just people of adapt to the new world and so we're still doing a lot of virtual work and people are responding and getting things done.

So I don't know that we've seen anything from Delta and I'm not sure of.

For Camille of something and say about patient <unk> and Delta.

At this point.

Eric: The only thing I would add is that patient identification has been pretty consistent over the last couple of quarters. And the other good thing to add about that is that we're finding more adult patients than pediatric patients and thus far, we have not seen any impact from the Delta variant, but it's very early.

The only thing I would add as debt.

The.

Type of patient identification and it's been pretty consistent.

The last couple of quarters and.

And the the other good thing to add about that and so we're finding more adult patients and pediatric patients and thus far have not seen any impact from there from the delta variant, but it's very early.

Camille L. Bedrosian: Right, this is Camille. I would agree with that. To Amel's point, the teams have been working virtually quite a bit as well as understanding more about the multi-generational aspects of the disease and finding patients in that way as well. Thank you, thank you. Good, Jeff. All right, next question.

Alright, this is Camille and I would agree with that and to analyst point the <unk>.

And this had been working virtually quite a bit as well as.

Understanding more about the multi generational aspects of the disease, and finding patients and that way as well.

Thank you guys. Thank you.

Alright next question.

Operator: The next question is from Jogetiyibir, Yol D'O'uio, and Yolome.

The next question is from Joel the deal with Baird. Your line is open.

Operator: Hi, thanks for taking the question. For Angelman, what gives you confidence that the changes you're making in dose administration will help reduce or avoid lower extremity weakness? And part of the reason I ask is that since it wasn't seen in pre-clinical studies, that may make it more difficult to test for. Certainly.

Hi, Thanks for taking the question for Angelman and what gives you confidence that the changes youre, making and dose administration will help reduce or avoid the lower extremity weakness and part of the reason I ask us it wasn't seen in preclinical studies that may make it more difficult.

Unknown Attendee: Certainly, but I think there are two things I would say, Joe. Based on non-clinical studies, we know the therapeutic window actually goes pretty low. So we know that in the single-digit range, we would see efficacy based on what we're seeing in the animal. So it gives us confidence that we could stay low and still get the potency, right? There's a therapeutic effect we would expect.

Thus far.

And certainly, but I think there's 2 things I would say Joe is that.

Based on non clinical studies, we know the therapeutic window actually goes pretty low so we know that in the single digit range.

We would see efficacy based on what we're seeing and the animals. So it gives us confidence that we could stay low and still get the potency right. There's the therapeutic effect, we would expect.

Amy: What we know so far is among the patients that got the lower dose early in the course, and there are only a few patients, right; they didn't seem to have the problem at all, and, in fact, their lower extremities were improving prior to the event. So, not only were they not having an average effect, but their lower extremity function was actually one of the first things that people were talking about, that they weren't falling down, they were able to walk uphill, they were walking on grass and not falling down.

What we know so far is among the patients that got the lower doses early in the course and there's only a few patients right.

They didn't seem to have the problem at all and.

And in fact, they're lower extremities, we're improving prior to the event. So the only way to they're not having an adverse effect. They are actually lower extremity function was actually 1 of the first thing for people were talking about the theme.

Weren't falling down there and we'll walk uphill, they're walking on grass and not falling down these kits fall down a lot. So when they stopped falling down and parents notice right because it's kind of normal for them.

Amy: These kids fall down a lot. So when they stop falling down, parents notice, right? Because it's kind of normal for them. So we think that at those early doses, we're seeing an improvement even before the effects are seen. So I think that's why we're pretty confident that lowering the extreme effects is not happening at lower doses because they wouldn't be getting better if you're having a safety event at the lower doses. So, the combination of those two features puts us in a position to believe that the lower houses will get the safety and appropriate administration, and we believe the Trindelmer and Flesh approach, which we're taking XUS, will optimize the delivery of the drug and make sure it's not sitting down at high concentrations locally, causing a chemical effect.

So we think that those early deals, we're seeing and improvement even before the effects of <unk>. So I think that's why we're pretty confident that Lawrence Jeremy thats not happening at lower doses, because they wouldn't be getting better if youre, having the safety events at the lower doses. So the combination of those 2 features and can put us and positioned to believe that the low doses will get the safety.

And the appropriate administration.

And we believe the trend of home refresh approach, we're taking ex US we will optimize the delivery of drug and make sure it's not sitting down and the high concentration of locally.

<unk> the chemical effect.

Got it thank you.

Operator: and your last question is from June Lee with tourist security.

And your last question is from Joon Lee with tourists Securities. Your line is open.

Operator: Hi, thanks for taking the follow-up question. So just to clarify, ML, you said that you saw no antibodies or cells implying that it's unlikely to be an adaptive immune reaction, which sort of assuages FDA's concern about redosing. But have you ruled out the formation of any, like, tertiary structures or, like, self-complementary of their GTX-1-2 that caused your innate immune responses? Because I'm just curious what sources of this could be what, that could be what, you may be worried about. Thank you. Well, yeah, thank you.

Hi, Thanks for taking the follow up question. So just to clarify I know you.

And you said that you saw no antibody for cells, implying that it's unlikely to the to be the adaptive immune reaction, which sort of of switches sba's concern on the dosing, but have you ruled out the formation of any tertiary structures or like self complementary of bear Gtx 1 of 2 of that made.

For your innate immune responses, because just curious what sources of.

And that could be what SBU and may be worried about.

Thank you well thank.

Thank you.

Unknown Attendee: From everything we evaluate, the only thing we're seeing is like localized inflammation; there's nothing systemic. So any structural thing you're talking about wouldn't necessarily just become a localized phenomenon, right? It should have been systemic because the drug gets absorbed. We can prove it to you. It's absorbed into the circulation, in significant concentrations, and it's going, it'll, as from the animals, as you know, it'll end up in the kidney and everywhere. So why would you have such a highly localized effect if you're really having this fundamental problem?

And from everything we value of the only thing we're seeing us like localized and inflammation. There's nothing systemic so any structure thing you're talking about wouldn't absolutely just.

Become of localized phenomenon and it should've been of systemic because the drug gets absorbed we can prove it to you it's absorbed and the circulation of significant concentrations and is going.

And as from the animal says you know lend up and the kidney and everywhere. So why would you have such a highly localized the fact, if you're really having the fundamental problems. So I really don't think of us anything about it that fits that story.

Unknown Attendee: So I really don't think there's anything about it that fits that story. And we've done a lot of work on innate immunity and otherwise. I actually agree with you because you don't see any effect in the brain itself, it's just local, so it's not like you.

And yeah, and a lot of work on the innate immunity and otherwise.

Actually I agree with you because you don't see any effect of the brain itself and you just local so it's not like you see of wherever the assets all of the glucose.

Amy: like you see it wherever the end since all the good is good.

Amy: Right, you only see it where the first place was applied, so that's why it's very concentration dependent. If it was a nucleotide targeting thing, which we, by the way, they did some detailed work on and showed it does not, but if it were, it should have been happening wherever the drug is, it doesn't; it is highly localized to just below T12 to L5, that area, not even up the cord, where you know the drug went there.

And you don't you only see it where the first places applied so it's why is the very concentration dependent if it was a nucleotide targeting thing, which we by the way. They did some detailed work on and show and it does not but.

And if it were it shouldn't be happening wherever the drug if it doesn't it is highly localized to just below T 12, 5 that area not even up the cord, where you know the drug went there so.

Amy: So, right, it wouldn't, you wouldn't see such a weird localized phenomenon. I think, that's why I think If you look at a lot of the data, the ASOs cause a non-specific toxicity thing. That's what this looks like to me, and it's concentration dependent. So we just need to stay below the threshold, and we'll get it. The specificity part is very potent. We just need to keep the other part, you know, managed. All, thanks.

It wouldn't you wouldn't see such a weird localized phenomenon and I think that's why I think.

If you look and a lot of the date of the ASR caused the non specific toxicity thing that's what this looks like for me.

And the concentration dependent and so we just need to stay below the threshold and we will get get of the especially the part is very potent and we just need to keep the other part and managed.

Thanks for the follow up thank you.

Amy: Thanks for the follow- Thank you.

Great.

And that concludes the Q&A session for today's conference call I will now turn the call back to Joshua Hager for additional or closing remarks.

Operator: And that concludes the Q&A session on this conference goal.

Joshua Higa: I will now turn the call back to Joshua Hes for additional or closing remarks. Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at IR and Ultrogenics.com. Thank you for joining us.

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

Operator: Ladies and gentlemen, this concludes today's conference call. You may now disconnect. Stay safe and well. Have a good day.

Ladies and gentlemen. This concludes today's conference call you may now disconnect and stay safe and well have a good day.

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