Q3 2021 Ultragenyx Pharmaceutical Inc Earnings Call
Operator: Thank you for standing by.
Thank you for standing by and welcome to the third quarter 2021 financial results incorporated Pete.
Operator: 2021 financial results will be incorporated at this time.
Operator: All participants are in listen-moud. After the speaker's presentation,
At this time, all participants are in listen only mode.
After the Speakers' presentation there'll be a question and answer session to ask a question. During this session you will need to press star one on your telephone keypad. If you require any further assistance. Please press star zero. Thank you I would like to hand, the conference over to Joshua <unk>. Please go ahead.
Operator: There will be a question and answer session.
Operator: To ask a question during the session, you will need to press Star 1 on your telephone keypad. If you require any further assistance, please press Thar Zero. Thank you. I would like to hand the conference over to Josh Ahika. Please go ahead.
Joshua Higa: Good afternoon, and welcome to the Ultrogenics Financial Results and Corporate Update Conference Call for the third quarter of 2021. We have issued a press release detailing our financial results, which you can find on our website at www.ultrigenics.com.
Good afternoon, and welcome to the Ultra <unk> financial results and corporate update conference call for the third quarter 2021, we have issued a press release detailing our financial results, which you can find on our website at ultra <unk> Dot Com I.
Joshua Higa: I am Josh Wahiga, Director of Investor Relations.
I am Josh where he got director of Investor Relations. Joining me on this call are handled Cacace, Chief Executive Officer, and President Camille Bedrosian, Chief Medical Officer, Eric Harris, Chief Commercial Officer, and Mardi Dier, Chief Financial Officer.
Joshua Higa: Joining me on this call are Amal Kakas, Chief Executive Officer and President, Camille Vrodrosian, Chief Medical Officer, Eric Harris, Chief Commercial Officer, and Marty Deere, Chief Financial Officer. I'd 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 the not limited to the types of statements identified as forward-looking in our 2020 annual 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 in the investors 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 in our 2020 annual report on Form 10-K that was filed on February 12 2021.
Quarterly report on Form 10-Q that will be filed soon.
And our subsequent periodic reports filed with the SEC.
It will all be available in the investors section on our website. 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.
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, see our periodic reports filed with the SEA.
Please note the 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 see our periodic reports filed with the SEC I'll now turn the call over to him.
Amal Kakas: I'll now turn the call over to you.
Amal Kakas: Thanks, Josh, and good afternoon, everyone. I'll start off by highlighting our continued execution across Ultrogenics' Broad Portfolio Clinical and Commercial Since our last call, we made substantive progress on two of our most significant clinical programs focused on larger, rare genetic diseases. The first of these is GTX-2, an antacens olgunucluclide that we are developing in partnership with genetics biotherapeutics for Angerman Syndrome. Over the last few months, we successfully concluded discussions with three regulatory agencies to get our Phase 1-study up and running again.
Thanks, Josh and good afternoon, everyone I'll start off by highlighting our continued execution across ultra again, it's a broad portfolio of clinical and commercial assets.
Since our last call we made substantive progress on two of our most significant clinical programs focused on larger rare genetic diseases.
The first of these is gtx one O two an antisense oligonucleotide that we're developing in partnership with genetics biotherapeutics for Angelman syndrome.
Over the last few months, we successfully conclude discussions with three regulatory agencies to get our phase one two study up and running again.
Amal Kakas: The XUS protocol initially dows with four patients with two monthly doses each before our data monitoring committee reviews available safety data. As previously guided, we anticipate providing a preliminary update on the study after this review, which is expected to be around here. The study will then continue to treat those first four patients with two more monthly doses and to enroll an additional eight patients. We plan to provide a more substantial readout from the study after day 128 for all 12 patients, which is expected in mid-22. Turning to the U.S.
The ex U S protocol initially doses for patients with two monthly doses each before our data monitoring committee reviews available safety data.
As previously guided we anticipate providing a preliminary update on the study. After this review, which is expected to be around year end.
AH study will then continue to treat those first four patients with two more monthly doses and to enroll an additional eight patients.
We plan to provide a more substantial readout from the study after day 128 for all 12 patients which is expected in mid 2022.
Amal Kakas: We expect to begin dosing patients under the revised protocol later this quarter. The dose in the U.S. is lower than XUS, but patients are restricted to the younger, smaller 4-8-year-old age group. Our experience with the first five patients previously treated suggests that younger, smaller patients can respond to treatment at this dose after drug loading with four repeated low doses over three months. For Wilson's disease, we've also begun enrolling participants in the baseline evaluation phase of our pivotal study, UX. UX7-01 is an AAB9 gene therapy of a specially designed copper transporter that can restore normal copper metabolism and distribution.
Turning to the U S. We expect to begin dosing patients under the revised protocol later this quarter.
The dose in the U S is lower than ex U S. But the patients are restricted to the younger smaller 48 year old age group our experience with the first five patients previously treated suggest that younger smaller patients can respond to treatment.
After drug loading with four repeated low doses over three months.
For Wilson disease, we've also begun enrolling participants in the baseline evaluation phase of our pivotal study U S. UX seven O. One is an AAV nine gene therapy of especially designed copper transport of that can restore normal copper metabolism and distribution.
Amal Kakas: The design of our novel Phase 1, study in Wilson disease is notable because it enables a seamless transition from a traditional dose-finding phase one-two study right into a pivotal study, which will save time. I will note that this is our fourth clinical stage gene therapy program and our first targeting a more prevalent genetic disease. Camille will provide more information on this program and study later on in her section.
The design of our novel Phase 123 study in Wilson disease is notable because it enables a seamless transition from a traditional dose finding phase one two study.
Right into a pivotal study, which will save time.
I don't know if this is our fourth clinical stage gene therapy program in our first targeting a more prevalent genetic disease.
Camille will provide more information on this program and study later on in her section.
Amal Kakas: Also of note is that the UX-1 program for Wilson disease is our second program to use the Ultigenics producer cell line or PCL gene therapy manufacturing system. PCL technology is a novel approach similar to vaccine manufacturing that is designed to yield a more productive and consistent AV production process. The result is that we are manufacturing commercial grade material at commercial scale for the first clinical patients with a substantial reduction in cost compared with the triple transfection process.
Also of note is that the U S 701 program for Wilson disease is our second program to use the ultrasonics producer cell line or P. C. L gene therapy manufacturing system.
<unk> technology is a novel approach similar to vaccine manufacturing.
It's designed to yield a more productive and consistent AAV production process.
Result is that we are manufacturing commercial grade material at commercial scale for the first clinical patients with a substantial reduction in costs compared with triple transfection processes.
Amal Kakas: This process allows us to manufacture enough material to treat all the patients randomized to UX701 in the phase 12 portion of the study with a single run, significantly driving down costs. An important element when thinking about the potential reimbursement challenges in the future for gene therapy products. We are continuing to invest in our PCL system, and most recently, it's part of our preclinical AAB program for Duchenne, Musker Dystrophy. We expect the greater productivity of the PCL system will be especially important for more common and higher dose indications like Duchenne, where the amount and cost of the product can be an important factor.
This process allows us to manufacture enough material to treat all the patients randomized to <unk> 701 in the phase one two portion of the study with a single run.
Significantly driving down Cogs and important element when thinking about the potential reimbursement challenges in the future for gene therapy products.
We're continuing to invest in our PCL system. Most recently as part of our preclinical AAV program for Duchenne muscular dystrophy, we expect the greater productivity productivity of the PCL system.
We will be especially important for more common and higher dose indications like duchenne, but the mountain cost the product can be an important factor.
Amal Kakas: Moving to the rest of our clinical pipeline, we are advancing four additional programs that further demonstrate the diversity of our portfolio across modality. All four of these programs have new studies starting over the next few months, and three of these studies will be pivotal.
Moving to the rest of our clinical pipeline, we are advancing four additional programs that further demonstrate the diversity of our portfolio across modalities.
All four of these programs have new studies starting over the next few months and three of these studies will be pivotal.
Amal Kakas: Our gene therapy for DTX 401 for GSD 1A and DTX301 for OTC deficiency are both moving into phase three studies based on durable, positive phase one two results over multiple years of follow-up. We are also on track for Pivotal Phase II, three study of our newest program, UX-4. This monoclon antibody will be tested in pediatric and adult patients with osteogenesis imperfective. A larger rare genetic bone disease complements the capabilities we've developed with Chris Vita.
Our gene therapy for <unk> hundred one for GSD, one a and D. T. O 301 for OTC deficiency are both moving into phase III studies based on durable positive phase two results over multiple years of follow up.
We're also on track to initiate a pivotal phase three study of our newest program U S. One for three.
This monoclonal antibody will be tested in pediatric and adult patients with osteogenesis imperfecta.
Our larger rare genetic bone diseases complements the capabilities, we've developed with Chris veto.
Amal Kakas: Upcoming with our commercial programs, despite the recent challenges with the COVID-Dalta variant, our team has continued to be effective at supporting compliance for patients already receiving our therapies, as well as increasing new patient starts across all products. With Chris Vita, the successful launch continues, and we're now tracking towards the upper end of our full year guidance. Dull patients are an increasing portion of patients we're identifying and converting to treatment. In Latin America, Krista continues to do especially well.
Wrapping up with our commercial programs. Despite the recent challenges caused by Covid Delta variant. Our team has continued to be affected that is supporting compliance for patients already receiving our therapies.
As well as increasing new patient starts across all products with.
Chris Vita.
A successful launch continues and we're now tracking towards the upper end of our full year guidance.
Adult patients are an increasing portion of patients we are identifying and converting to treatment.
In Latin America, Kristina continues to do especially well revenue in that region has more than doubled year to date in 2021 versus 'twenty 'twenty. This growth is backed by increases across the board in patient identification patients who have a prescription and are navigating reimbursement process and patients receiving reimbursed therapy.
Amal Kakas: Revenue in that region has more than doubled year to date in 2021 versus 2020. This growth is backed by increases across the board in patient identification, patients who have a prescription, and are navigating the reimbursement process, and patients receiving reimbursed therapy. We are nearing the conclusion of the formal reimbursement process in Brazil for access to the product, which should help further growth there. With Dols, we're continuing to build the momentum of a strong launch.
We are nearing the conclusion of the formal reimbursement process in Brazil for access to the product, which should help further growth there.
With Dol Dolby, we're continuing to build on the momentum of a strong lunch all the key metrics show. The teams are able to find patients and quickly get them on reimbursed therapy.
We're near 10% of the expected population of L. C. F O D patients now being prescribed <unk> in the first year or so of launch.
All of these are also growing in Europe, driven by significant increases in named patient requests in France and other countries in the region.
Amal Kakas: All the key metrics show the teams are able to find patients and quickly get them on reimbursed therapy. We're near 10% of the expected population of LCFOD patients now being prescribed to LZOV in the first year or so of launch. Dolobes are also growing in Europe, driven by significant increases in name patient requests in France and other countries in the region.
Before I turn the call over to Eric I wanted to highlight our recently announced collaboration with F. D. A NIH and leading public and private organizations focused on gene therapy development.
To be spoke gene therapy consortium as part of the NIH accelerating medicines partnership program is focused on advancing gene therapies for ultra rare diseases.
And yet ultra Jack we believe we have responsibility to support the development of treatments for as many rare diseases as possible, including these ultra whereas that might not otherwise get treated.
We also believe that this joint collaboration will help identify ways to improve the development process and create a further improved regulatory paradigm to improve the efficiency and effectiveness of the development of the next generation of gene therapies for all rare diseases.
Amal Kakas: Before I turn the call over to Eric, I want to highlight our recently announced collaboration with FDA, NIH, and leading public and private organizations focused on gene therapy development. The Bespoke Gene Therapy Consortium is part of the NIH Accelering Medicine Partnership Program. It's focused on advancing gene therapies for rare diseases. At Ultogenics, we believe we have a responsibility to support the development of treatment for as many rare diseases as possible, including these ultra-wheres that might not otherwise get. We also believe that this joint collaboration will help identify ways to improve the development process and create a further improved regulatory paradigm to improve the efficiency and effectiveness of the development of the next generation of gene therapies for all rare diseases. With that, I'll turn the call now over to Eric.
With that I'll turn the call now over to Eric.
Thank you Guillermo and good afternoon, everyone. The commercial and field teams continue to execute in the north and Latin American regions.
Right the ongoing pandemic.
This has led to another strong quarter building on significant momentum that was generated in the first half of the year.
The press release, we issued earlier today.
We further highlighted this by guiding towards the upper end of the $180 million to $190 million range for 2021 Cristina revenue.
Okay next territories, this would represent greater than 35% year over year growth.
Within the North American region, we continue to see steady underlying demand from both the pediatric and.
The adult markets as total number of prescribers surpassed 1000.
The split of the pediatric and adult patients remains approximately 50 50, while the total number of patients on therapy continues to increase.
Eric Harris: Good afternoon; the commercial and field teams continue to operate in North and Latin America despite the ongoing pandemic.
As Emil mentioned earlier, we expect the split will continue shifting towards a greater portion of adults and one placebo as a team.
To increase focus on finding doctors, who have adult patients with <unk> or CIO dispersed in the community setting.
Eric Harris: This has led to another strong quarter, building on significant momentum.
Eric Harris: The momentum that we generated in the first half of the year.
Compliance remains very high in part because of the auto care of patient support services team.
Eric Harris: In the press release we issued earlier today,
Because patients who began therapy recognize how much better they can feel went on Christina.
Eric Harris: We further highlighted this by guiding towards
Eric Harris: by guiding towards the upper end of the $180 to $180 million range for 2021 CRISPR revenue in ultrigenic territory. This would represent greater than 35% year-over-year growth. Within the North American region, we continue to see
Outside of the U S demand for Christina continues to gain momentum.
Third quarter revenue in Latin America.
Grew significantly versus the second quarter, partly reflecting uneven ordering patterns, we expect within that region.
However, if you compare the revenue of the first three quarters in 2021 versus the same period of time period. In 2020, you can begin to see the significant opportunity ahead of us.
Eric Harris: steady underlying demand from both the pediatric and adult markets as the total number of prescribers
Revenue over that time period grew approximately 115% driven by increasing underlying the night.
Eric Harris: prescribers surpassed 1,
Eric Harris: The split of the pediatric and adult patients remains approximately 50-50, while the total number of patients on therapy continues to increase. As AMO mentioned earlier, we expect this split will continue to shift towards a greater portion of adults on Cresita. As the teams continue to focus on finding doctors who have adult patients with
This is the result of the work the teams have been doing for the last couple of years educating health care providers.
Patients and work with regulatory and reimbursement authorities.
We are in the final stages of negotiating all reimbursement with the Brazilian authorities and in the meantime continue to receive orders from the Ministry of health.
Support patients who have been granted.
Eric Harris: of SLH or TIO dispersed in the community setting. Compliance remains very high, in part because of the ultracare of the patient support services team and because patients who begin therapy recognize how much better they can be.
You don't seem to receive this therapy.
Turning now to <unk>, which was approved for the treatment of long chain fatty acid oxidation disorders, or LC <unk> by the FDA in the middle of 2020 and by Health, Canada earlier this year.
Eric Harris: Better they can feel when on Chris Feta.
In the third quarter.
Eric Harris: Outside of the U.S., the man for Chris Vita continues to gain momentum, third-quarter revenue and Latin America through significantly versus the second quarter, partly reflecting the uneven ordering patterns we expect within their region.
We added approximately 40 stock loans, bringing the total since launch to approximately 310 start forms.
As of the end of the quarter. This has resulted in approximately 250 patients on reimbursed therapy.
Eric Harris: However, if you compare the
Approximately 145 unique healthcare providers have written a prescription for <unk>.
Eric Harris: of the first three quarters in 2021 versus the same time period in 2020, you can begin to see the significant opportunity ahead of us. Revenue over that time period grew approximately 115%
And we are continuing to see growth in the number who have written multiple prescriptions.
Much of the success, we have seen in the FERC of launches driven by a couple of factors first the <unk>.
Demand for the type of major centers Portland, born errors of metabolism.
Eric Harris: 15% is given by increasing underlying demand.
Eric Harris: This is the result of all the work the teams have been doing for the last couple of years to educate healthcare providers, find patients, and work with regulatory and reimbursement
Second our patient support services team is doing a great job supporting patients and their families as they navigate the insurance process and work through any issues they might have received.
Eric Harris: We are in the final stages of negotiating full reimbursement with the Brazilian authorities and, in the meantime, continue to receive orders from the Ministry of Health to support patients who have been granted an injunction to receive this therapy. Turning now to Djok, which was approved for the treatment of long-chadad
Overtime, we believe demand for the Adobe will continue to grow at a steady pace similar to other products in the space.
Outside of the U S uptake of the Dolby remains strong through our named patient and early access programs in Europe with yoga is growing driven by steady increases in named patient requests in France.
We are continuing to work with regional regulatory regulators to gain full approval to treat all patients who could benefit from the job in fact.
Eric Harris: or LCFAOD by the FDA in the middle of 2020.
Eric Harris: and by Health Canada in earlier issues.
The Brazilian National Health Surveillance Agency recently approved <unk> for the treatment of both pediatric and adult patients with LC <unk>.
Eric Harris: Canada earlier this year. In the third quarter, we added approximately 40 starforms, bringing the total finished launch to approximately 310 stars. As of the end of the quarter, this has resulted in approximately 250 patients on reimbursed therapy, and approximately 100,
As is typical with in that country. We are now working with the Ministry of finance to get full reimbursement approval.
These are important steps forward as we seek to provide broad access to Adobe and the Latin American region.
Eric Harris: 45 unique health care providers have
The teams look to close out the year, they will continue to adapt to the ever changing COVID-19 landscape. So ensure that patients continue to benefit from our products with that I'll turn the call over to Marty to share the financial results.
Eric Harris: description for the Jogi, and we are continuing to see growth in the number who have written multiple
Eric Harris: Much of the success we have seen in the first year of launch is driven by a couple of factors. First, there is strong demand for Jovey as a major center for inborn errors and metabolism. Second, our patient support services team is doing a great job, supporting patients and their families as they navigate the insurance process and work through any issues they might have and receive
Thanks Derek.
The press release earlier today that included a financial update which I will briefly summarize company revenue for the quarter ending September 30th 2021 totaled 81 point X million Kristina revenue in ultra Genex territories grew to $53 million.
Eric Harris: Over time, we believe the market for dodovi will continue to grow at a steady pace.
Eric Harris: a steady pace similar to other products in the space. Outside of the U. U. U. U. U. U. U. The Jalb remains strong through our name, patient, and early access programs. In Europe, the JOLDiv is growing, driven by steady increases in named patient requests in France.
Adding 40 point 43 million from the North American profit share territory, and net product sales of seven 4 million in other regions.
Total royalty revenue related to the sale of the crispy that in the European territory was $4.7 million.
Eric Harris: We are continuing to work with regional regulators to gain full approval.
The agility revenue for the quarter was $10 7 million.
We have stated before we will not be providing guidance printing TV in the first quarters of launch we believe the metrics Eric just discussed better describes the success we are seeing so far.
Eric Harris: to treat all patients who could benefit from Jody. The Brazilian National Health Surveillance Agency recently approved Adjogi for the treatment of both
Eric Harris: treatment of both pediatric and adult patients with LCFA
Net revenue for the third quarter of 2021 with $2 9 million and we expect these revenues may modestly increase overtime.
Eric Harris: As is typical within that country, we are now working with the ministry.
Third quarter 2021 revenue also includes 12 point $12 1 million related to the tech transfer as part of our strategic manufacturing partnership with Daiichi Sankyo around our PCL and Heck 293 technologies.
Eric Harris: with the ministry of finance to get full reimbursement approval.
Eric Harris: These are important steps forward as we seek to provide broad access to Dovey and the Latin American League. As the teams look to close out the year, they will continue to adapt to the ever-changing COVID landscape so that patients can continue to benefit from our product. With that, I'll turn the call over to Marty to share the financial wish.
As we have discussed previously and in the fourth quarter 2021.
Revenue, we recognized from the agreement will taper significantly as the tech transfer activities wind down as planned.
Maurice Thomas Raycroft: to share the financial results.
Maurice Thomas Raycroft: Thanks; we issued a press release earlier today that included financial information.
Additional details on this revenue recognition can be found in our annual and quarterly reports filed with the SEC.
Maurice Thomas Raycroft: That included a financial update, which I will briefly summarize. Company revenue for the quarter ending September 30, 2021, totaled 81.8.6 million. Krispita revenue in Ultigenics territories grew to 50.3 million, including 43 million from the North American profit share territory and net product sales of 7.4 million in other regions. Total royalty revenue related to the sales of Krispita in the European territory was 4. The Jolvie revenue for the quarter was 10.7 million. As we have stated before, we will not be providing guidance for DeJolvi in these first quarters of launch.
Total operating expenses for the quarter were $171 5 million, which includes research and development expenses.
Expenses of $113 4 million SG&A expenses at $53 9 million in cost of sales of $4 2 million.
We continue to expect our R&D costs to increase in 2021 compared to 2020, and we support three pivotal gene therapy clinical trials that you excellent for three phase three clinical study in Genesis and protector and the phase one two study for our most advanced mrna program <unk> three <unk>.
D train and a number of about their preclinical activities as they get ready to advance the next programs into the clinic.
Maurice Thomas Raycroft: We believe the metrics Eric just discussed better describe the success we are seeing so far. That's $70-million revenue for the third quarter of 2021 with $3.9 million, and we expect these revenues may modestly increase over time. Third quarter 2021 revenue also includes 12.1 million related to the tech transfer as part of our strategic manufacturing partnership with Daiichi Sankio around our PCL and HEC2-23 technologies. As we have discussed previously in the fourth quarter 2021, the revenue we recognize from this agreement will taper significantly as the tech transfer activities wind down as planned. Additional details on this revenue recognition can be found in our annual and quarterly reports filed with the SEC.
We also expect SG&A to modestly increase in 2021 as we compare as it continued to support the expansion of the lunch at the crispy that agility and Debbie.
For the quarter ended September 32021, net loss was $73 million or $1 eight per share. This compares to a net loss for the same period in 2020, and $68 8 million or $1 13 per share.
The net loss for the third quarter 2021 includes that $25 7 million increase in the fair value of investments and equity securities as compared to 11 million 11 5 million decrease in Q3 2020.
Net cash used in operations for the nine months ended September 32021, with $284 4 million compared to $69 8 million for the same period in 2020 net cash used in the nine months ended September 32021 includes the $50 million upfront payment for the closing of the morale.
Maurice Thomas Raycroft: Total operating expenses for the quarter were 171, which included research and development expenses of 113.4 million. SG&A expenses of 53.9 million and cost of sales of 4.2 million. We continue to expect our R&D costs to increase in 2021 compared to 2020 as we support three pivotal gene therapy clinical trials, the UX143, a Phase 23 clinical study in osteogenesis in Perfecta, and the Phase 12 study for our most advanced MRNA program, UX 053 in GSD3, and a number of other preclinical activities as we get We also expect SGNA to modestly increase in 2021 as we continue to support the expansion of the launches of Crospita, DeJovie, and Mepi.
License and collaboration agreement compared to the net cash used in the same period of 2020 that included $154 million.
Operating cash received from Daiichi Sankyo was related to the collaboration and license agreement.
We ended the third quarter with approximately $941 million in cash cash equivalence and marketable securities just pushed that puts us in a strong capital position to reach key clinical and commercial milestones as they continue executing our development and commercial strategy.
So now I'll, let Camille touch on some of our clinical programs Camille.
Maurice Thomas Raycroft: For the quarter ended September 30th, 2010, the net loss was $73 million or $1. This compares to a net loss for the same period in 2020 of $68.8 million or $113 per share. The net loss for the third quarter 2021 includes a $25.7 million increase in the fair value of investments and equity securities as compared to an 11.5 million decrease in Q3 2020. Net cash used in operations for the nine months ended September 30th, 2021, was $284.4 million compared to $69.8 million for the same period in 2020.
Thank you Marty and I too wish everyone a good afternoon.
Sure I share updates from our ongoing clinical programs I'd like to review new data that were presented last month at the international network for fatty acid oxidation research and management or inform 2021 virtual conference.
The results represent data over a longer period of time and an additional patients and an independent group of patients with long chain fatty acid oxidation disorders L. C. S E O D treated window Tobey in an extension study.
There was a statistically significant reduction in annualized major clinical events, our MCT ease and annualized duration of these events for 33 patients who had not previously received treatment with <unk> when comparing the 18 months prior to treatment to the media and 21 nine months on <unk>.
Maurice Thomas Raycroft: Net cash used in the nine months ended September 30th, 2021 includes the $50 million upfront payment for the closing of the Moreo License and Collaboration Agreement, compared to the net cash used in the same period of 2020, that included $154 million of operating cash received from Daiichi Sanquio related to the collaboration and license agreements. We ended the third quarter with approximately $941 million in cash, cash equivalents, and marketable securities. This puts us in a strong capital position to reach key clinical and commercial milestones as we continue executing our development and commercial strategies. So now, I'll let Camille touch on some of our clinical programs.
<unk>.
In these patients the median annualized rate of empty eased went from 2.00 to 0.28 per year or an 86% reduction.
P value of 0.0343.
And the median annualized duration of Sce's went from $8 6620, 0.8 days or at 91% reduction P value of 0.0325.
These data are consistent with the previous published results.
Next I'll shift to Gtx, one owe to the anti sense oligonucleotide, a ASO that we are developing in partnership with kinetics for the treatment of Angelman syndrome.
Camille L. Bedrosian: Thank you, Marty, and I too wish everyone a good afternoon. Before I share updates from our ongoing clinical programs, I'd like to review new data that were presented last month at the International Network for Fatty Acid Oxygen.
Angelman is a severe neuro genetic disorder that affects approximately 60000 patients in the developed world.
Camille L. Bedrosian: research and management, or inform 2021 virtual conference. The results represent data over a longer period of time and on additional patients in an independent group of patients with long-chain fatty acid oxidation disorders, LCF-A-O-D, treated with Dolvi in an extension
We with our partner genetics are currently enrolling the phase one two study in Canada and the U K.
Dosing at the Canadians site has already begun but the U K to follow shortly.
As a reminder, initially to patients in the under eight year old and two in the over eight year old cohort will be enrolled.
Camille L. Bedrosian: There was a statistically significant reduction in annualized major clinical events or MCEs and annualized duration of these events for 33 patients who had not previously received treatment with Dol Drovi when compared to the 18 months prior to treatment to the median.
Following each patient second monthly dose and the completion of a two week follow up period.
Data monitoring Committee will review the available safety data to determine if they recommend moving forward with enrolling the remaining four patients in each age cohort.
Following extensive discussions with the FDA, we were able to reach agreement on a modified protocol that will allow us to dose naive patients younger than eight years old in the United States.
Camille L. Bedrosian: 21.9 months on therapy. In these patients, the median annualized rate of MCE went from 2.00 to 0.28 per year, or an 86% reduction, P value 0.0343, and the median annualized duration of MCEs went from 8, to 0.8 days, or a 91% reduction.
The revised protocol will enroll eight patients split between a gtx 102 treatment arm and a comparator group with the active group receiving two milligrams monthly doses for four months.
The comparator group can then eventually enter the same dosing regimen.
Camille L. Bedrosian: P value 0.0325. These data are consistent with the previous published results. Next, I'll shift to GTX 102, the antisense ologonucleotide, ASO, that we are developing in partnership with genetics for the treatment of Angelman syndrome, a severe neurogenetic disorder.
Because the dose level is lower than the U S protocol, we have narrowed enrollment to the younger age patients four to eight years old.
The site in the U S has a number of patients identified who are all eager to participate in the study.
We expect dosing to begin later this quarter.
I'll now turn to our three pivotal gene therapy programs, starting with <unk> 701 for the treatment of Wilson disease.
Wilson disease is a rare genetic disorder of copper metabolism due to a mutation in the ATP 70, our copper transporter gene.
Camille L. Bedrosian: affects approximately 60,000 patients in the developed world. We, with our partner Genetics, are currently enrolling the Phase 1-study in Canada and the U. Dosing at the Canadian site has already begun, with the UK to follow shortly. As a reminder, initially, two patients in the under eight-year-old cohort and two in the over eight-year-old cohort will be enrolled following each patient's second monthly dose and the
This results in the accumulation of copper in the liver and brain, particularly and potentially progressive serious disease.
We estimate there are approximately 50000 patients in the developed world who have Wilson disease.
Last month, we announced that we have successfully screened the first patients in the seamless phase <unk> study that aims to directly address the mutated H P. P 70 gene.
Camille L. Bedrosian: After the completion of a two-week follow-up period, a data monitoring committee will review the available safety data to determine if they recommend moving forward with enrolling the remaining four patients in each age cohort. Following extensive discussions with the FDA, we were able to reach agreement on a modified protocol that will allow us to dose naive patients younger than eight years old in the United States. The revised protocol will enroll a patient split between a GTX-2 treatment arm and a comparator group, with the active group receiving two milligrams monthly doses for four months.
These patients are now in a six to 12 week baseline evaluation period, where they will be evaluated to ensure stable measures of disease, such as 24 hour urinary copper concentration complete blood count and liver function tests.
Following this baseline screening period patients will be randomized and treated with <unk> 701 or placebo.
Next D T X 401 for the treatment of glycogen storage disease type one a R. J S. D. One a is a disease that arises from a defect in the glucose six phosphatase or <unk> enzyme, which is essential to the livers ability to release glucose to the bloodstream and its deficiency.
Camille L. Bedrosian: The comparator group can then eventually enter the same dosing regimen. Because the dose level is lower in the U.S., we have narrowed enrollment to the younger patient group of 4 to 8 years old. The site in the U.S. has a number of patients identified who are all eager to participate in the study. We expect dosing to begin later this quarter.
Leads to serious hypoglycemia.
GSD one a is the most common genetically inherited glycogen storage disease with an estimated 6000 patients in the developed world.
We have a number of sites already activated and expect the first patients in the U S and Canadian sites to enter the four to eight week baseline evaluation period around the end of the year.
Camille L. Bedrosian: I'll now turn to our three pivotal gene therapy programs, starting with UX701 for the treatment of Wilson disease. Wilson disease is a rare genetic disorder of copper metabolism due to a mutation in the ATP7B or copper transporter gene. This results in the accumulation of copper in the liver and brain, particularly a potentially progressive serious disease. We estimate there are approximately 50,000 patients in the developed world who have Wilson disease. Last month, we announced that we had successfully screened the first patients in the seamless phase one, two, three study that aims to directly address the mutated ATP-7B gene. These patients are now in a six to 12 week baseline evaluation period where they will be evaluated to ensure stable measures of disease, such as 24-hour urinary copper concentration, complete blood count,
During this period patients will be monitored to established four consecutive weeks of clinically stable disease to the use of a controlled diet.
Oral glucose replacement therapy, and it continuous glucose monitoring.
Followed this baseline evaluation period patients will be randomized and treated with either <unk> or placebo.
Our third pivotal gene therapy is D. T X 301 for the treatment of ornithine <unk> or OTC deficiency.
OTC is a critical component of the urea cycle that metabolize as toxic ammonia into urea that can then be safely excreted in the urine.
Ammonia is a very potent toxic compound and can lead to coma.
Serious brain injury and death.
There are approximately 10000 patients in the developed world with 80% being late onset.
Camille L. Bedrosian: Following this baseline screening period,
Camille L. Bedrosian: During the screening period, patients will be randomized and treated with UX701 or placebo.
We currently expect the first patients to enter the four to eight week baseline evaluation period around the end of the year.
Camille L. Bedrosian: Next, DTX 401 for the treatment of glycogen storage disease type 1A, or GSD1, is a disease that
During this period patients will be monitored to established four weeks of clinically and metabolically stable disease two of them.
Camille L. Bedrosian: arises from a defect in the glucose 6thase or G6 pH
Protein restricted diet and or they use as ammonia scavengers.
Camille L. Bedrosian: enzyme, which is essential to the liver's ability to release bile
Following this baseline evaluation period patients will be randomized and treated with either <unk> or placebo.
Camille L. Bedrosian: glucose to the bloodstream, and its deficiency leads to serious hypoglycemia. GSD1A is the most common genetically inherited glycogen storage disease, with an estimated 6,000 patients in the developed world. We have a number of sites already activated and expect the first patients from the U. and Canadian sites to enter the 4-8-week baseline
The last program I will touch on is <unk> 143 for the treatment of osteogenesis Imperfecta R O I.
O I has a large genetic bone disorder with approximately 60000 patients in the developed world.
And most of our X L. H doctors have many more patients with Oi than X L. H.
These patients have reduced or abnormal collagen it triggers a maladaptive bone remodeling response.
Camille L. Bedrosian: baseline evaluation period around the end of the year.
The body recognizes the back collagen and breaks down bone and a repeat of cycling attempt to fix the issue.
Camille L. Bedrosian: During this period, patients will be monitored to establish four consecutive outcomes.
However, patients with Hawaii are unable to create normal collagen and that then leads to an over resorption and inadequate net production of bone and the bone weakness creates the risk for fractures.
Camille L. Bedrosian: Executive weeks
Camille L. Bedrosian: oral glucose replacement therapy, and a continuous glucose monitor. Following this baseline evaluation period, patients will be randomized and treated with either DTX 401 or placebo. Our third pivotal gene therapy is DTX301 for the treatment of or or otc OTC is a critical component of the urea cycle that metabolizes toxic ammonia into urea that can then be safely excreted in the urine. Ammonium is a very potent neurotoxic compound and can lead to coma, serious brain injury, and death.
What we have found in animal models is that if you stimulate the production of more bone with anti scar often or other agents you can improve the bone strength to normal or near normal even while the collagen is still mutated.
This would suggest that the facility of the bond is not due to the collagen, but it's actually the body's maladaptive response to this defect.
UX 143, or so tourism AD is a fully human anti <unk> monoclonal antibody that should help the body right. This imbalance by stimulating bone production and suppressing bone resorption.
Camille L. Bedrosian: There are approximately 10,000 patients in the developed world, 80% of whom are late onset. We currently expect the first patients to enter the four to eight-baseline evaluation period around the end of the year. During this period, patients will be monitored to establish four weeks of clinically and metabolically stable disease through a protein-restricted diet and or the use of an ammonia scavenger. Following this baseline evaluation period, patients will be randomized and treated with DTX-1 or placebo.
Restoring the net balance to our bone production.
Mario's asteroid study showed a dose dependent increase in <unk> and a decrease in CTX serum levels supporting this hypothesis.
There were also continuous improvements in bone mineral density over the 12 months treatment period of the study, including an 8% to 10% improvement in the spinal column, which is a better anabolic basalt and other commonly used bone anabolic agents.
The pivotal.
Two three study we expect to initiate later this year we'll.
Camille L. Bedrosian: The last program I will touch on is UX143 for the treatment of osteogenesis imperfecta, or OI. OI is a large genetic bone disorder with approximately 60 patients in the developed world. And most of our XLH doctors have many more patients with OI than XLH. These patients have reduced or abnormal collagen that triggers a maladaptive process.
We will study pediatric and young adult patients ranging from 5% to 25 years old with and without a history of prior bisphosphonate treatment.
The first part of the study will enroll approximately 40 patients and will evaluate a few doses compared to placebo.
Once the dose is identified the study will enroll additional patients at the optimal dose level.
Camille L. Bedrosian: a maladaptive bone remodeling response
Camille L. Bedrosian: The body recognizes the bad collagen and breaks down bone in a repeated cycling attempt to fix the issue. However, patients with OI are unable to create normal collagen, and that then leads to an over-resorption and inadequate net production of bone, and the bone weakness creates the risk for fracture. What we have found in animal models is that if you stimulate the production of more bone with antiskaroftin or other agents, you can improve bone strength to normal or near normal, even while the collagen is still mutated.
We will provide more details on the study design and endpoints when we initiate the study later this year.
With this update I will now turn back the call to Amy Thank you.
Thank you Camille.
Before we close out I'd like to provide a quick reminder of the key upcoming milestones for the company.
For Gtx 102 in Angelman syndrome, we've dosed patients in Canada will dose patients in the U K and U S. Later this quarter, we plan to provide a preliminary update on this program around the end of the year.
Camille L. Bedrosian: This would suggest that the fragility of the bone is not due to the collagen but is actually the body's maladaptor response to this. UX-143 or cetuzumad is a fully human antiskarostin monocon antibody that should help the body address this imbalance by stimulating bone production and suppressing bone resorption, restoring the net balance toward bone production. Moreo's asteroid study showed a dose-dependent increase in P1NP and a decrease in CTX serum levels.
For our gene therapy pipeline will continue enrolling the UX 701 Phase 123 study for Wilson will share longer term follow up phase.
<unk> two data at the ICA I am from the studies of <unk> hundred one in GSD, one and <unk> 301 in OTC.
We'll initiate phase III studies in both these programs around the end of 2021.
<unk> Jensen perfect.
We'll initiate the pivotal phase three study in pediatric patients around the end of the year with studies in other age groups anticipated to begin next year.
As you can see our clinical pipeline as one of the largest and most diverse in the rare disease space.
Camille L. Bedrosian: There were also continuous improvements in bone mineral density over the 12-month treatment period of the study, including an 8 to 10 percent increase.
And target the number of genetic diseases with significant unmet need.
With four pivotal studies enrolling in early 2022, and the Angelman program back up and running we look forward to updating you on our progress.
Camille L. Bedrosian: including an 8 to 10% improvement in the spinal column, which is a better animal result than other commonly used bone anabolic agents. The pivotal, two, three study we expect to initiate later this year We'll study pediatric and young adult patients ranging from 5 to 25 years old, and without a history of prior Bifascinate treatment.
With that let's move on to your questions. Operator, please provide the Q&A instructions.
Thank you.
That's a question give me pass star one on your telephone keypad. If you would like to withdraw. Your question you May press depend Kiki, we'll pause for just a moment to compile the Q&A roster.
Camille L. Bedrosian: The first part of this study will enroll approximately 40 patients and will evaluate a few doses.
And our first question comes from the line this doesn't Ahmed from Bank of America.
Camille L. Bedrosian: patients and will evaluate a few doses compared to placebo. Once a dose is identified, the study will enroll additional patients at the optimal dose level. We will provide more details on the study design and endpoints when we initiate the study later this year. With this update, I will now turn back the call to AML. Thank you, Camille.
Your line is now open.
Okay. Thank you guys good evening and thanks for taking my questions.
Two quick ones Emil.
Protein gene therapy for DMD.
Where do you think that there is the most room to differentiate from what potentially could be on the market. So for example at the latest updates it seems like the Raptor and Pfizer are now both expecting their phase III data.
Amal Kakas: Before we close out, I'd like to provide a quick reminder of the key upcoming milestones for the For GTX 102 and Angerman Syndrome, we have dosed patients in Canada and will dose patients in the UK and US later this quarter. We plan to provide a preliminary update on this program around the end of the year. For our gene therapy pipeline, we're continuing to enroll the UX701 Phase 123 study for Wilson. We'll share longer-term follow-up phase one-two data at ICIEM from the studies of DTX 401 in GST1 and DTX301 in OTC.
For their programs in the early part of 2023, obviously, we don't know what they would look like but let's say that they're both on the market before.
Your program, where do you see the biggest opportunity there and then quickly for the 701 program are you able to tell us what you expect the screen out rate to be for the AAV nine antibodies with patients that you are looking to enroll into the study.
Sure. So look on the DMD program, we know when we started we're well behind the two program leaders interrupt and Pfizer and so on.
Our goal is to come up with a better.
Combination micro dystrophin and vector along with the manufacturing process, we think will be superior.
Amal Kakas: We will initiate face-to-face studies in both these programs around the end of 2021. For UX-143 and Osteine Imperfecta, we'll initiate the pivotal phase two-three study in pediatric patients around the end of the year, with studies in other age groups anticipated to begin next year. As you can see, our clinical pipeline is one of the largest and most diverse in the rare disease space, targeting a number of genetic diseases with significant unmet needs.
And.
To do some other improvements related to how we administer the drug which we think can enhance the delivery.
The combination of factors I think will help us provide an improvement in our ability to look at development and improve the quality of the development strategy and endpoints and evaluations I think or another factor.
We thank all of the micros drove them to do work and I think there's room for further improvement and we have that opportunity as a fast follower, but we're well behind and we have a lot of work cut out for us. So we appreciate both companies or other companies are very capable, but we do think we have some angles on how to be superior to the other Duchenne program.
Amal Kakas: With four pivotal studies enrolling in early 2022 and the instrument program back up and running, we look forward to updating you on our progress. With that, let's move on to your questions. Operator. Please provide the Q&A instructions.
The 89 for 701, we haven't put out any information on the frequency, but we don't expect as being an important issue with regard to being able to enroll the study and execute so far already multiple patients have qualified so we haven't seen an issue.
Operator: Thank you. To ask a question, you may press Star 1 on your telephone keypad. If you would like to withdraw your question, you may press the Pound Key. We'll pause for just a moment.
Okay. Thank you.
And your next question from Yaron Werber from Cowen. Your line is now open.
Operator: We'll pause for just a moment to compile the K&A roster.
Congrats to everybody all the great progress thanks for the question.
Operator: And our first question comes from the line of Dazine Ahmed from Bank of America. Your line is now open.
Just really quickly on the gene therapy stuff as well.
I know him well can you just got up and running.
Tazeen Ahmad: Okay, thank you guys. Good evening, and thanks for taking my questions. Two quick ones, Eamil. For gene therapy for DMD, where do you think that there is the most room to differentiate from what could potentially be on the market? So, for example, the latest updates; it seems like Surrepta and Pfizer are now both expected.
They need to be able to expect any maybe preliminary updates from the phase one two next year and if so maybe when youre thinking that could be.
And then just for an GSD <unk> OTC it seems like Youre expecting to start dosing patients probably realistically early next year now so I just wanted to see if there is maybe anything of note that 10 of limited getting these up and running or rate of enrollment or anything like that that we should be aware of thanks very much.
Tazeen Ahmad: Now they are both expecting their phase three data.
Tazeen Ahmad: for their programs in the early part of 2023. Obviously, we don't know what they would look like, but let's say that they're both on the market.
Sure so for the first.
Phase one two Wilson data, we expect by late in the year, we should have.
Enough data on the phase one to that segment of the program to be able to talk about it but we can't yet commit to the exact timing of that data.
Tazeen Ahmad: Before your program, where do you see the biggest opportunity there? And then quickly, for the 701 program,
But that's what we're expecting and the phase one two data would be separately analyzed from the phase III, So which gives us a little bit more room to maneuver with regard to disclosing what we find but.
Tazeen Ahmad: Are you able to tell us what you expect the screenout rate to be for the AV9 antibody?
Tazeen Ahmad: The AAB9 antibodies with patients that you're looking to enroll in the study.
Amal Kakas: Sure, look, on the DMD program, we know when we started, we were well behind the two program leaders, Sirepta and Pfizer, and so our goal is to come up with a better combination of microdestrofen and vector, along with the manufacturing process we think will be superior, to make some other improvements related to how we administer the drug, which we think can enhance its delivery. So the combination of factors, I think, will help us provide Now, our ability to look at development and improve the quality of the development strategy and the endpoints and evaluations is another factor.
But we expect we should know the dose and have information about it by late in the year next year.
We expect it to enroll fairly promptly for Wilson. So there are a lot of patients we think our program as well as <unk>.
Rack or a one for patients and we've managed to work to make it as convenient as possible. So we could enhance enrollment.
With regard to OTC.
We made the decision that GSD, one in Wilson, and we're able to get going quicker. The challenge of OTC is we had some work we had to do with the agency regarding the Regenesis test in.
The involvement of the device division that FDA is C. D. R. H on that which led to some more conversations or just took more time to get through and right now I would say fever, and CRH are both strapped and overextending. It took more time than we would've liked.
Amal Kakas: You know, we think all the microstrophins do work, and I think there's room for further improvement, and we have that opportunity as a fast follower. But we're well behind, and we have a lot of work cut out for us, so we appreciate both companies, or the other companies are very capable. But we do think we have some angles on how to be superior to the other Deschenwe.
So that's the main thing is really getting up and running we have been doing patient diagnosis for all of our programs with our global team have lined up a lot of patients that we know are out there. So at least we we believe we should be able to help improve the actual enrollment process. Once we get started but it took a little longer to get through some of the regulatory steps for OTC that behind.
Amal Kakas: programs. With regard to AV9 for 701, we haven't put out any information on the frequency, but we don't expect it to be an important issue with regard to being able to enroll the study and execute it. So far, multiple patients have already qualified, so we haven't seen an issue.
And just now we are ready to get going but there is still.
That's the one main difference for OTC.
Okay, Great makes sense, thanks very much.
Your next question from Maury Raycroft of Jefferies. Your line is now open.
Hi, everyone. Congrats on the progress and thanks for taking my question I was just going to check in on Angelman.
Preliminary data for the four patients around year end can you set expectations on what we should be focused on how much follow up we should expect and will there be enough total drug administered to see some efficacy in determining safety has improved.
Operator: And your next question is from Yaron Werber from Cowan. Your line is now open.
Yaron Benjamin Werber: Congratulations everybody. All great progress. Thanks for the question.
Yaron Benjamin Werber: Just really quickly on the gene therapy stuff as well. So I know in Wilson, you just got up and running. Would we maybe be able to expect any maybe preliminary updates from phase one to next year? And if so, maybe when you're thinking that could be? And then just for GSD 1A and OTC, it seems like you're expecting to start dosing patients probably realistically early next year now.
Yeah, I think the main thing Youll see is that we'll talk about.
Patients dosed and you know what.
We're looking at with regard to safety at that time I, It's a little bit early on in the time course to know what the loading would be and.
There is there was a run in period, where these patients were started and that pushed out the amount of data, we will get but it'll be a good update on where we are with regard to any safety issues and where we go but so it'll give us a sense that everything is progressing I think but it would take we won't have a lot of efficacy information at that point in time because.
Yaron Benjamin Werber: So I just wanted to see if there's maybe anything that's kind of limited to getting these up and running or rates of enrollment or anything like that.
Yaron Benjamin Werber: of enrollment or anything like that that we should be aware of. Thanks very much.
A bit early.
We are guiding too, though that the 12 patients have full data coming mid year is really kind of the place where you'll get a real full field for loading.
Amal Kakas: Sure, so for the Phase 1-Wilson data, we expect by late in the year we should have enough data on the Phase 1-2, that segment of the program, to be able to talk about it, can't yet commit to exact timing of that data but that's what we're expecting and the phase one two data would be separately analyzed from the phase three so which gives us a little bit more room to maneuver with regard to disclosing what we find But we expect we should know the dose and have information about it by late in the year, We expected to enroll fairly promptly for Wilson, so there are a lot of patients. We think our program is a trackable one for patients, and we've managed to work to make it as convenient as possible, so we could enhance enrollment.
Six young and six old patients.
<unk> tight trading and well I think that'll be the best assessment.
Anyway, so far it's going well and we're pleased to get going.
Got it and as a quick follow up for you.
I'll provide an update on enrollment status at the year end update where you're at with the total of 12 patients.
Yes, we will talk about where we're at on status of the program.
That time, yes.
Okay. Thanks for taking my questions.
And your next question from Joseph Schwartz of.
SBB Leerink your line is now open.
Hi, I'm Jerry dialing in for Joe. Thank you for taking my question. My first one is on Angelman is there any more work you can do to help the FDA get comfortable with the risk benefit of dosing additional angelman patients at a higher dose.
Amal Kakas: With regard to OTCs, you know, we made the decision that GF1 and Wilson were able to get going quicker. The challenge with OTCs, we had some work we had to do with the agency regarding the urea genesis test and the involvement of the device division of FDA, CDRH, on that, which led to some more conversations which just took more time to get through. And right now, I would say CBER and CERH are both strapped and overextended, and it took more time than we would have liked.
Yes, well.
I think FDA is being.
Conservative with regard to the sense of safety and I think the thing that's going to help them is getting more data on the higher doses ex U S and comfort with the administration strategy.
Conference and that confidence in it but you know.
For them there is not much benefit in taking any risks. So we were able to get started it too which will give us some information associated we restricted because of that dose to be the young patients where the milligrams of loaded drugs should be significant enough to give an effect based on what we saw before.
Amal Kakas: So that's the main thing, is really getting up and running. We've been doing patient diagnosis for all of our programs with our global team. We have lined up a lot of patients that we know are out there, so at least we believe we should be able to help improve the actual enrollment process once we get started. But it took a little longer to get through some of the regulatory steps for OTC. That's behind us now, we're ready to get going, but there is still, that's the one main difference for OTC.
But we think that the dose ex U S is going to give us the safety and efficacy information, which we would use to.
To revise the U S program eventually.
This coming year. So I think clinical data is what's going to move the needle for FDA at this point and that's on track to get it.
Okay, Great and I guess as a follow on to that you've kind of touched upon it but I guess to what extent do you think that the FDA will consider learnings from your ongoing U K and Canada February you'll be able to dose higher.
Yaron Benjamin Werber: Okay, that makes sense. Thanks very much.
Operator: Your next question from Morriekraft of Jeffrey's. Your line is now open.
Maury Raycroft: Hi everyone, congrats on the progress, and thanks for taking my question. I was just going to check in on Angelman for the preliminary data for the four patients around year-end. Can you set expectations on what we should be focused on, how much follow-up we should expect, and will there be enough total drug administered to see some efficacy and definitive safety?
Have you had any conversations with the FDA about about about this.
Well you know.
I've done a lot of regulatory and one of the things I know that doesn't really work that well to ask some hypothetical questions.
Because they won't commit to anything so you can't say if data look good there will you do this they'd say well, let's see what that says I just it's not really a productive thing to ask them, so, but I know from our history and I can tell you I've gone on for other programs.
Maury Raycroft: Yeah, I think the main thing you'll see is that we'll talk about patients' doses and, you know, what we're looking at with regard to safety at that time. It's a little bit early on in the time, of course, to know what the loading dose would be, and there was a run-in period where these patients were started, and that pushed out the amount of data we'll get.
I've gone ex U S obtain more data on safety efficacy come back to the U S got their agreement and got those products approved alright, So I've done it four times before I think that's probably enough evidence that that strategy can work.
Okay, Great. That's very helpful. And then my second question is on the Wilson program I believe with a D check something no. One has an inducible promoter curious to know how it works and how it and have you learned anything from your experience with Gtx 401, which also has a feature although it's likely you know just rang and they are starting with kidney patients.
Amal Kakas: But it'll be a good update on where we are with regard to any safety issues and where we go. So it'll give us a sense that everything's progressing, I think, but it will. Take, we won't have a lot of efficacy information at that point in time because it's a bit early. What we are guiding to is that the 12 patients with full data coming mid-year is really kind of the place where you get a real full feel for loading, you know, six young and six old patients, maximally titrating, and, well, I think that'll be the best assessment. Anyway, so far, it's going well, and we're pleased to get going.
Or and there needed to be patient.
Blood glucose to Quebec.
Great overtime.
Being the first evil or any purple are collaborating amongst wilson patients or do you expect that they will achieve homeostasis right away to get the dose right.
Maury Raycroft: Got it, and as a quick follow-up, will you provide an update on enrollment status at the year-end update on where you're at with the total of 12 patients?
Yeah, well, we're depending on the dose to get to the right level, where there isn't an inducible feature in seven one then.
And I'm aware of the 401.
Maury Raycroft: Yeah, we'll talk about where we are at and the status of the program at that time.
It's not just to do for well, it's more of a regulation that is.
The 401 promoter includes all the normal.
Maury Raycroft: Okay, thanks for taking my question.
Signaling elements that you require to control your glucose correctly, you know for insulin and glucagon and cortisol and other things so that our transgene for collection and star disease will respond to your body's signals, which I think is extremely important in managing glucose correctly right you want a system that responds.
Operator: And your next question comes from Joseph Schwartz.
Joseph Patrick Schwartz: of SVB Lerick, Carolina is now open. Hi.
Joseph Patrick Schwartz: Hi, I'm Jerry Diling in for Joe. Thank you for taking our questions. The first one is on Angelman. Is there any more work you can do to help the FDA get comfortable with the risk benefit of dosing additional Angelman patients at a higher dose? Yes.
For the for the metal I and I don't think there is actually a particular need as long as youre getting enough metal transport excess will not harm you.
Amal Kakas: I think the FDA is being conservative in regard to the sense of safety, and I think the thing that's going to help them is getting more data on the higher dose of XUS and comfort with the administration strategy. We have confidence in it, but, you know, for them, there's not much benefit in taking any risk. So we're able to get started at two, which will give us some information, so we restricted it because of that dose to young patients, where the amy milligrams of loaded drugs should be significant enough to give an effect based on what we saw before.
Basically your body already regulates whether it's sending the copper to the bile or whether it's going to the golgi.
The Golgi as how it makes it a little plasm, if you need if you have excess it ends up going to the bile and so how much transport as president as long as I think is critical as it might be in a.
Minute regulation.
Okay.
Okay, great. Thank you called the classification.
And your next question from Gena Wang of Barclays.
Thank you for taking my questions I also have two short questions regarding <unk> and Julien.
And I'm just wondering how did the FTE pick the two milligram dose.
The thought process or data to.
Amal Kakas: But we think that the dose XUS is going to give us safety and ethics information, which we would use to revise the U.S. approval eventually this coming year. I think clinical data is what's gonna move the needle FDA at this point, and I think that's on track to get it.
To support that and then second question is just wanted to confirm for the year end update so we see for patient data with each of the three doses or two doses and then quickly I think of you comment a little bit just wondering what kind of safety data in terms of the phone.
Joseph Patrick Schwartz: Okay, and I guess as a follow-on to that, you kind of passed away.
Follow up or does that from ex U S. Do you think it will allow you to do is higher in the U S.
Joseph Patrick Schwartz: But I guess, to what extent do you think that the FDA will consider learning from your ongoing UK and Canada studies where you'll be able to dose higher? Have you had any conversations with the FDA about this?
Okay. So the two milligram dose is basically a level that's 110th of the dose at which we saw in one patient safety problem remember patient five had the safety problem at 20, Megs and they wanted to have more dose 110th of that dose that's the basis.
Amal Kakas: Well, you know, I've done a lot of regulatory work, and one of the things I know that doesn't really work that well is to ask them hypothetical questions because they won't commit to anything. So you can't say, if the data look good there, will you do this? They'd say, well, let's see what that says. I just don't think it's really a productive thing to ask them. So, from history, and I can tell you, I've gone on four other programs; I've gone XUS, obtained more data on safety and efficacy, come back to the US, got their agreement, and got those products approved.
For that choice to make.
I don't really think that two to three three is a big difference, but they preferred to stay a full 10 tax below.
We decided just tactically not to try to titrate alright, they didn't tell us not to but we just decided not to even push it because.
We're going to get what we needed ex U S and it felt to us more important to just to get started and started treating some dose some patients and we restricted to the young patients because we felt we had a better chance of seeing efficacy in that group and the idea is we would have a group of patients now.
Amal Kakas: All right, so I've done it four times before. I think that's probably enough evidence that that strategy can work. Okay, great, that's very helpful. And then my second question is about the Wilson program. I believe that DTX-701 has an inducible promoter. Curious to know how it works and how, and have you learned anything from your experience with DTX 401, which also has this feature? Although it's likely, you know, different, and there still needs to be patients for, and they're needed to be patients, but glucose to quibylase.
For patients that would run at two Meg and will have ex U S. Patients. So two makes it get about a total of eight in the ex U S patients will get <unk>.
Around 16.6, Meg so we'll actually essentially have like a.
Equivalent of a sort of a half of the dose.
Cohort. So if you look at totality of this it will give us the potential for looking at dose response, combining U S and ex U S. Data. So there is a plus side to it and we think it's just about getting started in the U S and the FDA just wanted to be conservative and protect patients and we're willing to work with them and get through that and get onto the next step.
Amal Kakas: Equilibrate over time.
Amal Kakas: for any collaboration amongst Wilson patients, or do you expect that they will achieve homeostasis right away to get the dose rate? Yeah, well, we're depending on the dose to get to the right level. There isn't an inducible feature in 711 that I'm aware of. The 401, it's not just a do-it's more of a regulation that is. The 401 promoter includes all the normal signaling elements that you require to control your glucose correctly, you know, for insulin and glucose gone, cortisol and other things, so that our trans gene for collection and star disease will respond to your body's signals You want a system that responds to your needs.
And we're comfortable that dose administration change, we're making in our managing dose ex U S will be successful and therefore, we'll be able to bring that to the U S. At the end of the year update we've been.
We will have some safety data and.
Through the first few.
Two to three doses, but I think right now it won't it's not going to be a very complete update there'll be some dosing you'll get a sense of whether patients are having the symptoms, but we want to build a fully loaded the patients. We had hoped to have more like three to four doses, but it's more like two to three.
And the update I think it will give people comfort should if we're showing safety than we will at least understand that we can dose at this level and not get the problem and to get loaded efficacy that we think we need several doses in order to get there. So the efficacy will be.
Amal Kakas: For the metal ion, I don't think there is actually a particularly need. As long as you're getting enough metal transport, excess will not harm you. Basically, your body already regulates whether it's sending the copper to the bile or whether it's going to the Golgi. The Golgi is where you make seruloplasm. If you have an excess, it ends up going to the bile. And so how much transport is present and is not, I think, as critical as it might be in glucose minute regulation. Okay, great.
We'll provide what we have but it will be more important I think to look forward to the.
The full data set on 12 patients mid year, which will be I think a truly substantial amount of information on what's going on with that I'll go with.
At the dosing and load that we're proposing.
One last item you said safety data ex U S.
I think the type of safety will be able to show them is that we're not seeing the.
<unk> ratio protein into the CSF that we had seen and the fact that we're not seeing lower extremity weakness via both clinically as well as easing the neurological assess.
Amal Kakas: Okay, great, thank you for the clarification. And your next question is from Gina Wong of Berkeley.
Gena Wang: Thank you for taking my questions. I also have two short questions regarding Enderman.
Assessments and of course, if we saw a problem we would do an MRI scan so.
Gena Wang: So, Amy, just wondering how the FDA picked a 2 milligram dose, the thought process or data to support that? And then, a second question is, I just wanted to confirm for the year-end update. So will we see four patient data with each having three doses or two doses? And then quickly, I think you commented a little bit, just wondering, you know, kind of safety data in terms of, say, follow-up or dose that from XUS, do you think it will allow you to dose higher in the U.S.?
But assuming we haven't seen anything it's the combination of.
The laboratory and clinical findings that we'll be able to use.
In terms of justifying what will you do in the U S, but we'd expect to take the data from the majority of patients in the U S and after we've gotten our four doses loaded in those U S patients.
To put that package together and come back to FDA in order for the next.
Cohort.
In that we would initiate.
To begin at a dosing.
<unk> plan that would be more.
Optimal for achieving efficacy.
Yeah.
Great. Thank you.
And the next question from card person that of J P. Morgan. Your line is now open.
Gena Wang: Okay, so the 2 milligram dose is basically a level of one-tenth of the dose at which we saw a safety problem in one patient. Remember, patient five had the safety problem at 20 mix, and they wanted a dose one-tenth of that dose. That's the basis for that choice at 2Mibb. I don't really think that 2 to 3.3 is a big difference, but they prefer to stay a full
Great. This is Thomas on for Cory. Thanks.
The question I guess, maybe just a quick one on the chosen Niobrara X 133 and <unk>.
You guys haven't laid out the whole design of the phase III study there, but curious if you can just comment on what specifically you'll be looking for in the phase two portion to make a decision on the go forward dose.
And then also curious if we should be expecting a data update from the phase two portion of that slightly specifically thank you.
Amal Kakas: We decided just tactically not to try to titrate, right? They didn't tell us not to, but we just decided not to even push it because we were going to get what we needed XUS and it felt to us more important just to get started and start treating some patients, and we restricted ourselves to the young patients because we felt we had a better chance of seeing efficacy in that group. And the idea is we would have a group of patients now, four patients that would run at 2-mig, and we'll have ex-us patients, so two-migs that get about a total of 8, and the ex-us patients will get around 16.6 mig, so we'll actually essentially have like the equivalent of sort of a half of the dose cohort.
Sure. So the phase II portion will focus on P. One M P which is.
The synthetic peptides that were released when your bodies, making collagen and laying down new bone. So its the early sign of newborn creation and we will rely on that we have seen it before it provided a dose response, we will be looking at 'twenty and a higher dose and that's what we're trying to figure out for the children, whether a higher dose might work.
Better and so it's not only just thought which doses to dose range and age.
Page four dosing that we'll figure out we use a couple of dosing in the first group of patients that are in the phase one stage.
Amal Kakas: So if you look at the totality of this, it'll give us the potential for looking at dose response combining U.S. and X-U.S. data. So there is a plus side to it, and we think it's just about getting started in the U.S. and the FD.S.
Two parties to make the.
Decision and then define a dosing algorithm for children up to adults that we would use in the pivotal study. We know the 20 mid per kilo dose provides a substantial improvement in bone marrow density already in hand, so we have a strong anchor for wasn't effective dose.
Amal Kakas: The FDA just wants to be conservative and protect patients, and we're willing to work with them and get through that and get on to the next step. And we're comfortable that the dose administration change we're making and how we're managing dose XUS will be successful, and therefore, we'll be able to bring that to the U.S. The end of the year update, we've been, we will have some safety data through the first two to three doses, but I think right now it won't be a very complete update.
It's just about making sure we do the best we can for the children and we optimize and assure that there isn't more efficacy that we would have.
Missed out on by not increasing the dose either for children or adolescents are older patients.
So that's the basic idea with that we'll move into the rolling the phase III patients and.
At the using the dosing algorithm defined.
Okay. Thank you.
Next question from solving rich curious Goldman Sachs.
Amal Kakas: It will be some dosing; you'll get a sense of whether patients are having the symptoms, but we won't have to fully load the patients. We had hoped to have more like three to four doses, but it's more like two to three, and the update, I think, will give people, should, if we're showing safety, then we'll at least understand that we can dose this level and not get the problem.
Hey, good evening, guys and thank you for taking our question. This is Elizabeth on first olivine.
Just wanted to ask and I could have missed it but are you looking to start dosing patients that were originally treated.
And the Engelman This program and I guess, one could that happen.
We have not yet reached agreement on re dosing those patients.
If the agency wants us to treat these other patients and do a little more work to figure out whether we can demonstrate it safe to re doses patients.
Amal Kakas: And to get to efficacy, though, we think you need several doses in order to get there. So the efficacy will be, you know, we'll provide what we have, but it will be more important to think about, to look forward to the full data set on 12 patients mid-year, which will be, I think, a truly substantial amount of information on what's going on with that ALGO at the doses and loads that we are proposing.
We believe its safe that problems have resolved fully.
And we do not think there is any hematological type.
Basis for what's going on but right now we have not received a plan to re dose those five patients, but we will work on that but our first step. We think is getting patients dosed in treated safely with that in hand. Then you can also go back and talk about re dosing. Those initial patients there were anxious to get started.
We have to work through this first step of treating some naive patients before we can make that move.
Amal Kakas: Last item, you said safety data, XUS. I think the type of safety data we'll be able to show them is that we're not seeing the exacerbation of protein into the CSF that we had seen, and the fact that we're not seeing lower extremity weakness viable clinically, as well as using neurological assessments. And, of course, if we saw a problem, we would do an MRI scan. But assuming we haven't seen anything, it's the combination of the laboratory and clinical findings that we'll be able to use in terms of justifying what we would do in the U.S.
Great. Thank you.
Next question from Hugo <unk> of Citigroup.
Is now open.
Hi, Thank you very much for taking my questions and congrats on the progress I just had a quick one on.
Could you tell us what the volume of the two milligram doses and have you ruled out the injection volume.
Isn't that was playing a role and he observed muscle weakness I'm, assuming it's not volume related.
Is this perhaps a piece of it.
Tenant effects based on the <unk> three a sequence or just the result of any antisense oligos present in Louisiana.
Yeah. So volume is not really a factor we've been yeah.
Using.
Amal Kakas: But we'd expect to take the data from the majority of patients in the U.S., and after we've gotten our four doses loaded in those patients, put that package together, and come back to FDA in order for the next cohort that we would initiate to begin at a dosing plan that would be more optimal for achieving efficacy.
10 cc and in some cases, they got more of a <unk>.
But it really didn't relate to the volume of the artificial CSF being used. So you don't think volume is a factor at all.
We do think though that.
That in these patients if they were there since they were relatively active patients they wouldn't lay down and they stood up quickly the drug tentative settled down in the bottom of their cord, which we think was probably a factor in.
Operator: And the next question is from Karri Kasimut of Jep Morgan.
Karri Kasimut: of J. J. Morgan, your line is now open.
Karri Kasimut: Great, this is Thomas speaking on behalf of Corey. Thanks for taking the question. I guess maybe just a quick one on Satruzumab or EX-143. I know you guys haven't laid out the whole design of the Phase 2 study there, but I'm curious if you can just comment on what specifically you'll be looking for in the Phase 2 portion to make a decision on the Go Forward Dose. And then also curious if we should be expecting any data
In incubating their nerve roots and a much higher concentration of drug.
Now we don't think its secret specific everything we've done would suggest that's not we think it's a high concentration of effective and was seeking specific we would've seen that phenomenon and up and up and down the spinal cord because the clinical effect happening in the brain demonstrates that the sequence is there, but yeah, we don't see the problem.
The drug in the colleague was originally heavily screened for sequence dependent effects and screen negative in toxicologist Lee was negative. So we don't think it's sequence specific fact at all thing it's nonspecific.
Karri Kasimut: I am expecting a data update from the phase two portions that's specifically. Thank you. Sure, so the phase two portion will focus on.
And at this point.
My best sense is that this is more of.
Our chemical irritation effect of the I'll go present at high concentrations in kids that don't lay down.
Amal Kakas: Sure, so the phase two portion will focus on P1MP, which is the synthetic peptides that are released when your body is making collagen and laying down new bone. So it's an early sign of new bone creation.
In the U K and Canada, now, we're today and even longer keeping them laying down and turned ellenburg and to make sure. The drug is moving forward. We're also adding a flush.
To keep the drug moving and make sure it mixes and rather than settling in at the bottom of their fine. So.
Amal Kakas: And we'll rely on that, we have seen it before, as a dose response. We'll be looking at 20 and a higher dose, and what we're trying to do is figure out for the children whether a higher dose might work better. And so it's not only just, it's not which dose, it's the dose range and age for dosing that we'll figure out; we'll use a couple of doses in the first group of patients that are in phase one, two parts to make the decision and then define a dosing algorithm for children up to adults that we would use then in the pivotal study.
That's what we think at the moment and we don't think it's sequence are volume dependent.
Okay got it thanks, and then just a separate question on <unk>.
Could you just comment on why you believe an antique fluoroscopy antibody would be a better approach and osteogenesis imperfecta as opposed to one of the commercially available radko antibody.
Well the rank all stuff like Denosumab. The data were not that great. The truth is they're they're blocking resort and more but the drill deficiencies and antibody anabolism, making bone.
The final difference in blocking resort.
Is that you are also inhibiting the overall turnover of bone in the correct way that is resolving them as needed and making new bond that is needed. When you look at what's happening in these patients, they're not making enough new bone their bonds are essentially off the product they are not making enough, they're resorbing too much not making enough new bone. So you really want an anabolic age.
Amal Kakas: We know the 20-mig per kilo dose provides a substantial improvement in bone roll density already in hand, and so we have a strong anchor for what's an effective dose. So this is just about making sure we do the best we can for the children and that we optimize and assure that there isn't more efficacy that we would have missed out on by not increasing the dose either for children or adolescents or older patients. So that's the basic idea. With that, we will move into rolling out phase three patients and using the dosing algorithm to find
And the anabolic agents. The reason it's important is that there are activating normal mechanisms in your bone and what are the bone gets laid down will be driven by where the signals are for billing weakness.
So when you have bone movement, there is a mechanism biological maxim to detect that weakness and movement and recruit the osteoblasts to make off decides to make new bone. So the whole mechanism is designed to fill inbound where its weakest.
Amal Kakas: from Salvin Rich Ter of Goldman Sachs, Head of Goldman Sachs. Hey, good evening, and thank you for taking our question.
And in animal models. This this particular mechanism.
Result of normalizing bone strength within a few weeks of treatment in a model with defective collagen. So it is a potential fundamental impact on bone and it's why we've been guiding people away. The idea that the weakness of bone and Oi is due to the collagen, but rather it's due to the maladaptive response, primarily.
Operator: Hey, good evening, and thank you for taking our question. This is Elizabeth from Salveen. Just wanted to ask, and I might have missed it, but are you looking to start redosing patients that were originally treated?
Salveen Jaswal Richter: We have not reached agreement on redoing those patients. The FDA agency wants us to treat these other patients and do a little more work to figure out whether we can demonstrate it's safe to redose those patients. We believe it's safe, the problems have resolved fully, and we do not think there is any immunological basis for what's going on.
And that that adapter response causes bonds to be resolved too much and not a bone to be made and so it <unk> the right biological signals a turn on bone production.
And it has some anti resort those effects too, but it's primarily an anabolic agent. We think could have a profound effect on oi and we think of all the mechanisms out. There. We think this is the strongest one because it drives osteoblast treatment and production of new bone.
Amal Kakas: But right now, we have not received a plan to redose those five patients, but we will work on that. But our first step, we think, is getting patients dosed and treated safely. With that in hand, then you can also go back and talk about redoing those initial patients. They're anxious to get started, but we have to work through this first step of treating some naive patients before we can make that move. Great, thank you.
Both are being effective for a life.
Great. Thank you.
Your next question from Julie asked you raised your line is now open.
Alright, thanks for the updates on the questions can you provide any more granularity granularity on the patient disposition from the first three cohorts is a lack of urgency by the FDA to allow re dosing based on from continued maintenance fee or is that something else and I have a follow up.
Salveen Jaswal Richter: Next question from Yigo Natts, from the CD group. My name is now open.
Well, there's no lack of urgency it's been urgently working and getting those patients retreated as his last November so if anything it's a.
Operator: Have you ruled out that injection volume was playing a role in the observed muscle weakness? And assuming it's not volume related, was this perhaps a sequence-dependent effect based on the UVE3A sequence or just the result of any antique scents illegal present in this DNA? Yeah, so volume is not really a factor. We've been using 10 cc, and in some cases, they got more 15 cc, but it really didn't relate to the volume of the artificial CSF being used, so we don't think volume is a factor at all.
Pure frustration for us because it should have happened.
I think the agency is we've provided all the data we have would show.
There really is no mechanism other than a local irritation contact kind of injury.
And.
However, we have in their mind definitly proven that and so there was a question what is going on.
But based on what we see there is definitely only evidenced re dosing.
We'd like to start doing but I don't think at this point, it's the right step forward for the agency I think we treat some patients with low doses show, we can do it safely show, we're getting efficacy and then re approached them with the concept of re dosing.
Yigal Dov Nochomovitz: We do think, though, that in these patients, since they were relatively active patients, they wouldn't lay down, and they stood up quickly, that the drug tended to settle down the bottom of their cord, which we think was probably a factor in incubating their nerve roots in a much higher concentration of drugs. Now, we don't think it's sequence-specific. Everything we've done would suggest it's not.
I think showing that we can get this done safely will help us.
Move forward on re dosing.
But fortunately, but didn't happen right away.
The patients continue to maintain for efficacy or have they gone back to baseline.
Amal Kakas: We think it's a high concentration effect. Even with sequence specific, we would have seen the phenomenon up and down the spinal cord because the clinical effect happening in the brain demonstrates the sequence is there. But yeah, we don't see the problem.
Well they did they.
They maintain their improvements for four or five months and.
Most of them have moved toward baseline in some ways, but I've heard from the pie that in fact, some of the patients have retained long term some of the benefits. They obtained during the treatment period. So it is possible that once the neurons have communicated and trained that they can actually maintain some of the signaling an improvement.
Amal Kakas: The drug and the colleague were originally heavily screen for sequence-dependent effects, and the screen negative, and toxicologically was negative. So we don't think it's sequence-specific fact at all.
So that's encouraging so they're not all the way back to baseline for some of the features but clearly they're not as good as they were when they were on Doug.
Amal Kakas: I think it's non-specific, and at this point, my best sense is that this is more of a chemical irritation effect of the oligo, present at high concentrations, and kids that don't lay down. In the UK and Canada now, we're sedating them longer, keeping them laying down in Trindellenberg, and to make sure the drug is moving forward, also adding a flush. That's just to keep the drug moving and make sure it mixes rather than settles in at the bottom of their spines. So that's what we think at the moment, and we don't think it's sequence or volume-dependent.
Okay.
And the second question is do you have any plans to vector right Gtx 102 looked like Jim Wilson is working with faster development spectrum rights and micro RNA targeting.
Can you be create etfs.
There is another company using vector I shorthair, Ernie probably I would say.
And I don't think so.
Just curious your long term plans I notice that it's not that it's a tricky Lucas.
Well, it's tricky locus and when you do it vector eyes is totally unregulated. So the challenge right now and we're doing gene therapy in the brain. We are working on <unk> deficiency, and we have a lot of work on it but I can tell you, though is the reliability of getting all the neurons treated efficiently consistently it's tougher with gene therapy.
Amal Kakas: Okay, thank you, and then just a separate question on petrusumab. Could you just comment on why you believe an antisplorosin antibody would be a better approach in osteogenesis imperfecta as opposed to one of the commercially available rantial with antibodies? Well, the rank-all stuff like denosemap, the data were not that great.
You end up with some new Orleans with a lot of expression and it's important to get enough expression in all and not too much in some and so and keep in mind that the only imprinted cells of the neurons not the other cells. So.
Amal Kakas: The truth is they're blocking resorption more, but the drill deficiency is in an anabalism, making bone. The final difference in blocking resorption is that you are also inhibiting the overall turnover of bone in the correct way, that is, resorbing bone that's not needed and making new bone that is needed. When you look at what's happening in these patients, they're not making enough new bone. Their bones are essentially osteoporic; they're not making enough, they're resorbing too much, not making enough new bone.
So there is some complexity as to how this would work when you don't know that the efficiency of gene therapy in the brain is going to be good enough for.
Angelman in terms of how what fraction neurons are truly transformed.
And so I would actually say that the sales strategies are more likely to treat more neurons consistently and will be more effective and that there is still work to be done I know everyone wants to vectra is and try to do that but.
Amal Kakas: So you really want an anabolic agent, and the anabolic agent, the reason it's important is that they're activating normal mechanisms in your bone, and where the bone gets laid down will be driven by where the signals are for building weakness. So when you have bone movement, there is a mechanism to detect that weakness and movement and recruit the osteoblast to make osteocytes and make new bone. So the whole mechanism is designed to fill in bone where it's weakest, and in animal models, this particular mechanism can result in normalizing bone strength within a few weeks of treatment in a model with defective collagen.
How many of them gotten there where they actually are a reliably controlling that in a wide variety of neurons in a consistent way. The brain is tricky I think DSO strategy. We're using is going to provide a more consistent result.
Going forward in <unk>.
With time, there's no question with time could there be a gene therapy, yes.
At that point, we will hope to be in position to be able to do it ourselves, but right. Now we're very excited about potential of an ASO that can bring benefit and help establish standards. What you can expect by turning on paternal <unk>.
Thanks.
Amal Kakas: So it is a potential fundamental impact on bone. And it's why we've been guiding people away from the idea that the weakness of bone in OI is due to the collagen, but rather it's due to the maladaptive response primarily, and that adaptive response causes bones to be resorbed too much and not enough bone to be made. And so sclerosin is the right biological signal to turn on bone production, and it has some anti-resorative effects, too, but it's primarily an anabolic agent.
Your next question comes back and heart of Stifel. Your line is now open.
Good evening, Thanks for taking our questions just two from me as well.
Going back to Angelman. So first on the U K and Canada protocol given that it includes the trend ellenburg as well as the artificial CSF flush.
I guess, we're mostly concerned about safety from the inflammation side of the question, but I was just wondering what the artificial CSF flush in a way kind of truncate. How soon you can actually see the efficacy signal and perhaps even at lower doses than what you might have seen in the first U S trial.
Amal Kakas: We think it could have a profound effect on OI, and of all the mechanisms out there, we think this is the strongest one because it derives osteoblast recruitment and production of new bone, both of which are being effective or alive.
And then second question related to Angelman as we think about the U S trial I know, it's flat dosing, but it also doesn't include artificial CSF flushed, nor the trend ellenberg.
Operator: Your next question from June Lee of tourist.
Joon So Lee: All right, thanks for the updates on the question. Can you provide any more granularity on the patient disposition from the first three cohorts? Is the lack of urgency by the FDA to allow redosing based on continued maintenance of XC, or is there something else? Can I have a follow-up?
So when we think about the spinal canal any reason to believe that.
Compared to the $3 three that any kind of efficacy that could emanate from these accumulated dose would be somewhat weaker than the U K with a Canadian patients. Thank you.
Amal Kakas: Well, there's no lack of urgency. It's been urgently working, getting those patients retreated since last November, so if anything, pure frustration for us because it should have happened. I think the agency is, we've provided all the data we have which show that there really is no mechanism other than a local irritation contact kind of injury. However, we have definitely proven that, in their minds, and so there is a question about what is going on. But based on what we see, there's definitely only evidence.
Yeah, so the Delaware and flush will enhance delivery to the brain and we know this is true and it's been true for other drugs by the way even chemo drugs by doing it now and we're gonna plus you will enhance brain concentrations. So that's kind of not new that's like three decades old. So it's not a unusual thing what's happening basically as you're enhancing the mix.
And the article stuff will not reduce it will reduce the local concentration, but it just enhances mixing so does the drug doesn't fit at high concentrations down in the lumbar area, but gets mixed into the body and volume of CSF and keeps the concentration down to the lower better so its about enhancing its about limiting lower concentration, but it's about.
Amal Kakas: Redosing is something we'd like to start doing, but I don't think at this point it's the right step forward for the agency. I think we need to treat some patients with low doses, show we can do it safely, show we're getting efficacy, and then re-approach them with the concept of redosing. I think showing that we can get this done safely will help us move forward on redososers. But fortunately, it didn't happen right away. The patients continue to maintain
Getting mixing once you mix the brain delivery will be improved in the U S. We're doing a lower dosing, where we're maintaining the original protocol in terms of patients laying down we're not doing turndown Limburg and flush it.
And.
It could reduce the delivery of drugs.
Amal Kakas: to maintain some efficacy, or have they gone back to the baseline?
We will get still drug delivery, but I would say, it's not going to be.
Amal Kakas: Well, they did, you know, they maintained their improvements for four or five months. Most of them have moved toward baseline in some ways, but I've heard from the PI that, in fact, some of the patients have retained long term some of the benefits they obtained during the treatment period. So it is possible that once the neurons have communicated and trained, they can actually maintain some of the signaling and improvement. So that's encouraging, so they're not all the way back to baseline for some of the features, but clearly, they're not as good as they were when they were on Doug.
It's not going to matter and fundamentally the drivers for choice choosing where administration that because it will come from our ex U S program. The U S patients will have a chance to see some efficacy and my hope would be we bring all that data together in the U S patients ex U S patients will get synchrony.
Synchronize on our developments on a treatment strategy for dose and administration going forward in next year.
Got it thank you very much.
Your next question from Geoff Hi, It's Morgan Stanley.
Thanks for taking the questions last quarter, you said you hadn't seen any impact from delta bearing on identifying new patients for Christina <unk> did you see any impacts on identifying patients and if so do.
We believe that the main impact from Delta variant is behind us.
Amal Kakas: Okay, and then, the second question is, do you have any plans to vectorize GTS 102? You know, it looks like Jim Wilson is working with FAS to develop vectorized microRNA targeting the same UB3AAAAAA.
Well I don't know if we've ever said.
That COVID-19 didn't have any impact on page things. It certainly had more of it last year for sure.
Easing up early in the year, the Delta probably had some impact in the year, but we feel like things are picking up and we're in pretty good shape in terms of how many patients we've diagnosed and in filling the pipe, but we see things is picking up again, and so delta probably had some impact on our ability to do face to face patient.
Joon So Lee: and there's another company using Vectori, Short Hair, Target, Same, you know, so just curious about your long-term plans. I know it's not a tricky look. Well, Tricy Locus and
Amal Kakas: Well, TRECELOCUS, and when you do it vectorized, it's totally unregulated. So the challenge right now, and we're doing gene therapy in the brain, we are working on CKL5 deficiency, and we have a lot of work to do on it. What I can tell you, though, is the reliability of getting all the neurons treated efficiently consistently is tougher with gene therapy. You end up with some neurons with a lot of expression, and it's important to get enough expression in all and not too much in some. And so, and keep in mind that the only imprinted cells are the neurons, not the other cells. So there are some complexities to how this would work.
Gnosis and find work.
But right now we don't see that as our biggest barrier, but things are improving.
Okay. Thanks, and then for <unk> 701, you said that you might not be able to treat all 50000 patients in the developed world, but what do you need to senior studies to be clinically meaningful and then I guess at that level, what proportion of the 50000 patients do you think would be addressable.
Yeah, what I've said is that.
Advise people not to include in their model that we would treat every known patients with Wilson disease gene therapy, I don't think that's rational.
I think youre going to end up finding.
The most urgent addressed patients or those with continuing problems difficulty complying.
Aggression, there are symptoms and it's a fraction of them and we've said it could be.
Amal Kakas: We don't know that the efficiency of gene therapy in the brain is going to be good enough for in terms of what fraction of neurons are truly transformed. And so I would actually say that ASO strategies are more likely to treat more neurons consistently and will be more effective, and that there's still work to be done. I know everyone wants to vectorize and try to do that, but let's see how many of them get there where they actually are reliably controlling that in wide-arive neurons in a consistent way. The brain is tricky.
A fractionally half of them or something but we don't really know what the number is and I would right now wouldn't want to speculate I think it's going to depend on what does the efficacy really looked like how powerful is it in the various types of severity Wilson disease patients.
If the duration of copper distribution has a bigger impact on neurologic function than than we know today that could change that.
Amal Kakas: I think the ASO strategy we're using is going to provide a more consistent result going forward. But with time, there's no question. With time, could there be gene therapy? Yes. At that point, we hope to be in a position to do it ourselves. Right now, we're very excited about the potential of an ASO that can bring benefits and help establish standards for what you can expect by turning on paternal UB3A.
The outcome of how many patients get on therapy, but I've told people. The biggest early addressable patients would be the ones that are still having problems even on key layers or unable to tolerate them and I think that would be true for almost any of the gene therapies that that's going to really be dependent on people who are needing improvement.
To justify it and I just think we shouldn't model assuming a huge fraction of all of these patients are going to get treated I don't think it's rational but.
Operator: from Dagon Haas of Stissell: Your line is open.
We do think there's a really significant fraction of those patients in.
Dae Gon Ha: Good evening, thanks for taking our questions. Just two from me as well, going back to Angelman.
I believe that we're storing copper distribution will be more important than people realize today.
Thank you.
Dae Gon Ha: So first, on the UK and Canada protocols, given that it includes the Trindlenberg as well as the artificial CSF flush. I guess we're mostly concerned about safety on the inflammation side of the question. But I was just wondering, would the artificial CSF flush, in a way, kind of truncate how soon you can actually see the efficacy signal and perhaps even at lower doses than what you might have seen in the first U.S. trial?
Your next question from S true Zelda U B S.
Hi, Thanks for taking my question apologize, if I'm asking things you've already covered.
Jumping between calls, but did show me can you comment on the sequential changes in the new start forms versus the total treated patients.
Kind of look at the sequential numbers it looks like the stock farm seem to be pretty stable quarter over quarter.
Dae Gon Ha: And then second question related to Angelman, as we think about the U.S. trial, I know it's flat dosing, but it also doesn't include our official CSF flushed nor the Trindelenberg. So when we think about the spinal canal, any reason to believe that, you know, compared to the 3, any kind of efficacy that could emanate from these accumulated doses would be somewhat
But there is variability on changes in the total number of patients treated.
Any color you can share on that would be helpful. And then I have a quick follow up on Gtx, one I can.
Eric are you available do you want to talk about that particular topic.
Sure I mean first and foremost I think it's important to note that the team has done a remarkable job launching this product.
The pandemic.
See steady growth in all the key Mexico start forms reimburse patients in total number of patients to some other.
Dae Gon Ha: We are weaker than the UK or the KK.
Dae Gon Ha: with a Canadian patient. Thank you.
Amal Kakas: Yeah, so the Trindalmurg and flush will enhance delivery to the brain, and we know this is true, and it's been true for other drugs, by the way, even chemo drugs. By doing Trindal and Bergen flush, you will enhance brain concentration, so that's kind of not new. That's like three decades old.
A number of prescribers that.
Multiple prescriptions. So we believe these are the best indicators.
We've already stated.
And the other thing I think it's important to note that in the first year of launch.
We have about 10% of the estimated permanent population on reimbursed treatment.
Always stated as we move into 2021 through 2021, we expect a steady gradual build.
Amal Kakas: So it's not an unusual thing. What you're doing, basically, is you're enhancing mixing, and the artificial stuff will not reduce, it will reduce the local concentration, but it just enhances mixing so that the drug doesn't sit at high concentrations down in the lumber area. but gets mixed into the volume of CSF and keeps the concentration down, the lower, the better. So it's about enhancing, it's about limiting lower concentration, but it's about getting mixing. Once you mix them, the brain delivery will be improved. In the U.S., we're doing a lower dose. We're maintaining the original protocol in terms of patients laying down. We're not doing Trindon-Berg and flush.
Consistent with other products and I think that's what you're seeing is.
Steady gradual growth.
All forward.
Eric I think she is speaking of the there's a slight lag in the reimbursed patients from the Q3, but I think this was in the summer Delta variant. It was probably a a package to some of the thing.
Everybody can look at that.
Those patients are just working themselves through the reimbursement process and.
We fully expect them to be able to transition on to treatment.
Reimbursement remains strong.
Amal Kakas: It could reduce the delivery of drugs. I think we'll still get drug delivery, but I would say it's not going to be. It's not going to matter. Fundamentally, the drivers for choosing administration efficacy will come from our ex-US program. The U.S. patients will have a chance to see some efficacy, and my hope would be that we bring all that data together, and the U.S. patients and the ex-U.S. patients will get synchronized on a development strategy for dose and administration going forward next year. Got it. Thank you very much.
Excess.
We've had the same pattern during chriss feed or where we have more to start forms kind of continuing and reimbursement a little lagging them catching up again and I don't think there's anything there I think the key thing start forms is growing and reimbursement totals are growing so we feel good about.
The strength and continued progress in the launch.
Okay, and what is the average durability I know it's early days in launch, but are you sort of seeing patients sticking to therapy for the course of the year or.
Another way to ask is what is the drop off rate.
We I think we've been seeing people stay on therapy. In fact, we have people who've been on the drug almost 20 years now steadily so.
Dae Gon Ha: Your next question comes from Jeff Hong of Morgan Stanley.
Operator: Thanks for taking the questions. Last quarter, you hadn't seen any impact from the Delta variant on identifying you.
In our trials, we lost a few people to very beginning but when we learned how to adapt and dietitian to help guide people how to get started we've generally seen people stay on drug very long periods of time I don't know I don't think we've put out specific numbers yet at this point, Eric but no we haven't but we have to put us listen this persistence.
Jeff Hung: on identifying new patients for Cresita. In 3Q, did you see any impact on identifying patients? And if so, do you believe that the main impact of the Delta variant is behind us?
Jeff Hung: Well, I don't know if we've ever said that COVID didn't have any impact on patients, I guess. It certainly had more of it last year, for sure, and it started easing up early in the year.
It's been presented.
Consistent yeah.
Got it and then on <unk> one.
102.
Jeff Hung: The Delta probably had some impact this year, but we feel like things are picking up, and we're in pretty good shape in terms of how many patients we've diagnosed and in filling the pipe. But we see things as picking up again, and so Delta probably had some impact on our ability to do face-to-face patient diagnosis and find work. But right now, we don't see that as our biggest barrier, but things are improving. Okay, and then for UX701, you said that you might not be able to treat all 50,000 patients in the developed world. What do you need to see in your studies to be clinically meaningful?
Can you clarify whether false.
Four patients have already been dosed in Canada, or when would that be completed.
We haven't said we have we have.
Multiple patients dosed and the process is ongoing so we would expect to have.
All patients have got all four patients would've gotten dosing and more than one dose.
But we'll put out more information at the end of the year exact timing. It just depends on what happens with each center, but it's going along well and we're happy with the number of patients that are queued up ready to go.
Got it thank you.
Again to ask a question you May press star one on your telephone keypad.
Jeff Hung: And I guess at that level, what proportion of the 50,000 patients do you think would be addressable? What I've said is that I advise people not to include in their model that we would treat every known patient with Wilson disease with gene therapy. I don't think that's rational, think you're going to end up finding the most urgently addressed patients, so those with continuing problems, difficulties with coping with progression, their symptoms. And it's a fraction of them, and we've said it could be, you know, a fraction of half of them or something, but we don't really know what the number is. And I, right now, wouldn't want to speculate.
And your last question from Joel Beatty of Baird.
Your line is now open.
Hey, Thanks for taking my question could you tell us more about the manufacturing runs youre getting with the TCR gene therapy system.
In particular.
Quantifying the size of the runs as well as the percent of empty capsid is youre, saying.
Yeah, the the PCL system runs at a 2000 liter scale.
Alright, and disposals 2000 liter bioreactors and depending on the particular PCL clone where in the.
Jeff Hung: I think it's going to depend on what the advocacy really looks like, how powerful it is in the various types of severity of Wilson's disease patients. If the restoration of copper distribution has a bigger impact on neurologic function than we know today, that could change the outcome of how many patients get on therapy. But I've told people the biggest early-addressable patients would be the ones still having problems, even on chelators, or unable to tolerate them.
Usually in the 60% to 80% full range.
Fault compared to empties.
And so it's a lot higher than you would see with triple transfection methods. That's the raw product and then you would go through purification.
Yeah.
Great. Thank you.
And that's good there Kenny session I would now like to turn it back to Josh for final remarks.
Thank you. This concludes today's call. If there are any additional questions. Please contact us by phone IR Ultra <unk> dot com.
Jeff Hung: And I think that would be true for almost any of the gene therapies. It's going to really be dependent on people who are needing improvement to justify it. And I just think we shouldn't model assuming a huge fraction of all these patients are going to get treated. I don't think it's rational. But we do think there's a really significant fraction of those patients. I believe that restoring copper distribution will be more important than people realize today. Thank you. Your next question is from Esther Rahavala of
For joining us.
Yeah.
Yes.
[music].
Operator: Hi, thanks for taking my question and I apologize. I'm asking things we've already covered.
Okay.
[music].
Esther Rahavala: I've been jumping between calls, but on DeJolvi, can you comment on the sequential changes in the new start forms versus the total number of patients treated? When I kind of look at the sequential numbers, it looks like the start forms seem to be pretty stable quarter over quarter, but there's variability in changes in the total number of patients treated.
Esther Rahavala: So any color you can share on that would be helpful. And then I have a quick follow-up on GTX-10. Thank you.
Esther Rahavala: Yeah, Eric, are you available? Do you want to talk about that particular topic?
Eric Harris: Sure, first and foremost, I think it's important to note that the team has done a remarkable job launching this product in the midst of the pandemic. You know, we see steady growth in all the key mechs with Starform.
Eric Harris: reimburse patients and the total number of patients, a number of patients, a number of
Eric Harris: other number of prescribers that have multiple prescriptions.
Eric Harris: Indicators. We've always stated, and the other thing I think is important to note in the first year,
Eric Harris: note In the first year of launch, we had about 10% of the estimated prevalent population on reimbursed treatment. We always stated as we moved into 2021 through 2020, we expected a steady gradual rise in the bill, continue consistent with other products, and I think that's what you're seeing is a steady gradual growth as
Eric Harris: Eric, I think she's speaking of the, there is a slight lag in the reimbursement of patients in Q3, but I think this was in the summer Delta variant. It was probably impacting some of the things. Yeah, if you look at that, those patients are just working themselves through the reimbursement process,
Eric Harris: We fully expect them to be able to transition on to treatment as reimbursement remains strong.
Eric Harris: Access for that. We've had the same pattern during Chris Fida, where we have more to start forms kind of continuing and reimbursement a little lagging and then catching up again. And I don't think there's anything there. I think the key thing, starting forms, is growing, and reimbursement totals are growing. So we feel good about it, and we are making strength and continued progress in the launch.
Esther Rahavala: And what is the average durability? I know it's early days in the launch, but are you sort of seeing patients sticking through therapy for the course of the year or another way to ask if there is a drop-off?
Eric Harris: We have, I think we've been seeing people stay on therapy. In fact, we have people that have been on the drug for almost 20 years now, steadily. In our trials, we lost a few people at the very beginning, but when we learned how to adapt and use dietitians to help guide people how to get started, we've generally seen people stay on the drug for very long periods of time.
[music].
Eric Harris: I don't know, I don't think we've put out specific numbers yet at this point, Eric, but no. No, we haven't put out any specific numbers. Persistent, yeah. It's been to do.
Esther Rahavala: Got it. And then on GTX 1022, can you clarify whether all four patients have already been seen?
Esther Rahavala: Four patients have already been dosed in Canada, or when will that be completed? We haven't said.
Amal Kakas: multiple patients dose, and the process is ongoing. So we'd expect to have All patients have got, all four patients would have gotten doses and more than one dose. But we'll put out more information at the end of the year, exact timing. It just depends on what happens at each center. But it's going along well, and we're happy with the number of patients are queued up ready to go.
Operator: Again, to ask a question, you may press store 1 on your telephone keypad. And your last question from Joel Bidre.
Joel Lawrence Beatty: Hey, thanks for taking the time to ask a question. Could you tell us more?
Joel Lawrence Beatty: about the manufacturing runs you're getting with the PCL, in the therapy system, in particular
Joel Lawrence Beatty: therapy system, in particular, quantifying the size of the runs as well as the percent
Joel Lawrence Beatty: Yeah, the PCL system runs at a 2,000-scale scale, all right, and disposal 2, bioreactors. And depending on the particular PCL clone, we're usually in the 60 to 80% full range, full compared to empty. And so it's a lot higher than you would see with triple transaction methods. That's the raw product, and then you would go through purification.
Joshua Higa: And I'd get some good out of our session. I would like to turn it back to Josh Wahiga for final remarks. Thank you. This concludes today's program.
Joshua Higa: Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at irautechonics.com. Thank you for joining us.
Joshua Higa: and so on. Thank you, and the and and Thank you, The and and and and and and You and You and You.
Operator: the third quarter, financial results, and corporate, Pete at this time.
Joshua Higa: All participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press Star 1 on your telephone keypad. If you require any further assistance, please press Thar Zero. Thank you. I would like to hand the conference over to Josh Hika. Please go ahead.
Joshua Higa: Good afternoon, and welcome to the Ultrigenics Financial Results and Corporate Update Conference Call.
Joshua Higa: for the third quarter of 2021.
Joshua Higa: We have issued a press release.
Joshua Higa: detailing our financial results, which you can find on our website at ultrgenics. I am Josh Wahiga, Director of Investor Relations.
Joshua Higa: Joining me on this call are Amal Kakas, Chief Executive Officer and President, Camille Brodrosian, Chief Medical Officer, Eric Harris, Chief Commercial Officer, and Marty Deer, Chief Financial Officer. I would like to remind investors that this call will include forward-looking statements within the meaning of the safe harbor provision.
Joshua Higa: of the Private Securities Litigation Reform Act of 1995, including but not limited to the type
Joshua Higa: types of statements identified as forward-looking in our 2020-
Joshua Higa: Our 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.
Joshua Higa: These forward-looking statements represent our views only as at 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, see our periodic reports filed with the SEC.
Joshua Higa: I'll now turn a call over
Amal Kakas: Thanks, Josh, and good afternoon, everyone. I'll start off by highlighting our continued execution across Ultrogenics' Broad Portfolio Clinical and Commercial Assets. Since our last call, we have made substantive progress on two of our most significant clinical programs focused on larger, rare genetic diseases. The first of these is GTX-2, an antacens algonucluclide that we are developing in partnership with genetics biotherapeutics for Angerman
Amal Kakas: Over the last few months, we successfully concluded discussions with three regulatory agencies to get our Phase 1-study up and running again. The XUS protocol initially doses four patients with two monthly doses each before our data monitoring committee reviews the safety data. As previously guided, we anticipate providing a preliminary update on the study after this review, which is expected to be around here. The study will then continue to treat those first four patients with two more monthly doses and to enroll an additional eight patients. We plan to provide a more substantial readout from the study after day 128 for all 12 patients, which is expected in mid-22. Turning to the U.
[music].
Amal Kakas: We expect to begin dosing patients under the revised protocol later this quarter. The dose in the U.S. is lower than XUS, but patients are restricted to the younger, smaller 4-8-year-old age group. Our experience with the first five patients previously treated suggests that younger, smaller patients can respond to treatment at this dose after drug loading with four repeated low doses over three months. For Wilson's disease, we've also begun enrolling participants in the baseline evaluation phase of our pivotal study, UX. UX701 is an AAB9 gene therapy of a specially designed copper transporter that can restore normal copper metabolism and distribution.
Amal Kakas: The design of our novel Phase 1, study in Wilson disease is notable because it enables a seamless transition from a traditional dose-finding phase one-two study right into a pivotal study, which will save time. I will note that this is our fourth clinical stage gene therapy program and our first targeting a more prevalent genetic disease. Camille will provide more information on this program and study later on in her section.
Amal Kakas: Also of note is that the UX-1 program for Wilson disease is our second program to use the Ultrigenics producer cell line or PCL gene therapy manufacturing system. PCL technology is a novel approach similar to vaccine manufacturing that is designed to yield a more productive and consistent AV production process. The result is that we are manufacturing commercial grade material at commercial scale for the first clinical patients with a substantial reduction in cost compared with the triple transfection process.
Thank you for standing by and welcome to the third quarter did that then in 'twenty, one financial results and corporate update at this time all part.
Amal Kakas: This process allows us to manufacture enough material to treat all the patients randomized to UX701 in the phase one-two portion of the study with a single run, significantly driving down costs. An important element when thinking about the potential reimbursement challenges in the future for gene therapy products. We are continuing to invest in our PCL system, and most recently, it's part of our preclinical AAB program for Duchenne, Muscat Dystrophy. We expect the greater productivity of the PCL system will be especially important for more common and higher dose indications like Duchenne, where the amount and cost of the product can be an important factor.
Disciplines are in listen only mode. After the speaker's presentation there'll be a question and answer session to ask a question. During this session you will need to press star one on your telephone keypad. If you require any further assistance. Please press star zero. Thank you I would've liked to hand, the conference over to Joshua.
Please go ahead.
Good afternoon, and welcome to the Ultra <unk> financial results and corporate update conference call for the third quarter 2021.
Amal Kakas: Moving to the rest of our clinical pipeline, we are advancing four additional programs that further demonstrate the diversity of our portfolio across modalities. All four of these programs have new studies starting in the next few months, and three of these studies will be pivotal.
<unk> issued a press release detailing our financial results, which you can find on our website at ultra <unk> Dot com.
I'm, Josh where he got director of Investor Relations joining me on this call our ammo pack as Chief Executive Officer, and President Camille Bedrosian, Chief Medical Officer, Eric Harris, Chief Commercial Officer, and Mardi Dier, Chief Financial Officer, I would like to remind investors that this call will include forward looking statements within the meaning of the safe Harbor provision.
Amal Kakas: Our gene therapy for DTX 401 for GSD 1A and DTX301 for OTC deficiency are both moving into phase three studies based on durable, positive phase one, two results over multiple years of follow-up. We are also on track for Pivotal Phase II, three study of our newest program, UX-4. This monoclon antibody will be tested in pediatric and adult patients with osteogenesis imperfective. A larger, rare genetic bone disease complements the capabilities we've developed with Chris Vita.
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 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 the investors section on our website. 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.
Amal Kakas: Upcoming with our commercial programs, despite the recent challenges with the COVID-Dalta variant, our team has continued to be effective at supporting compliance for patients already receiving our therapies, as well as increasing new patient starts across all products. With Chris Vita, the successful launch continues, and we're now tracking towards the upper end of our full year guidance. Adult patients are an increasing portion of patients we are identifying and converting to treatment. In Latin America, Krista continues to do especially well.
The actual results could differ materially from those projected in any forward looking statements for a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward looking statements as well as risks related to our business see our periodic reports filed with the SEC I'll now turn the call over to him.
Thanks, Josh and good afternoon, everyone.
Amal Kakas: Revenue in that region has more than doubled year to date in 2021 versus 2020. This growth is backed by increases across the board in patient identification, patients who have a prescription, and are navigating the reimbursement process, and patients receiving reimbursed therapy. We are nearing the conclusion of the formal reimbursement process in Brazil for access product, which should help further growth there. With Del Jolvi, we're continuing to build the momentum of a strong launch.
Start off by highlighting our continued execution across ultrahigh, its broad portfolio of clinical and commercial asset.
Since our last call we made substantive progress on two of our most significant clinical programs focused on larger rare genetic diseases.
The first of these a gtx one O two an antisense oligonucleotide that we're developing in partnership with genetics biotherapeutics for Angelman syndrome.
Over the last few months, we successfully conclude discussions with three regulatory agencies to get our phase one two study up and running again.
The ex U S protocol initially doses for patients with two monthly doses each before I data monitoring committee reviews available safety data.
Amal Kakas: All the key metrics show the teams are able to find patients and quickly get them on reimbursed therapy. We're near 10% of the expected population of LCFOD patients now being prescribed LZOV in the first year or so of launch. Dolzobes are also growing in Europe, driven by significant increases in name patient requests in France and other countries in the region.
As previously guided we anticipate providing a preliminary update on the study. After this review, which is expected to be around year end.
The study will then continue to treat those first four patients with two more monthly doses and to enroll an additional eight patients we plan to provide a more substantial readout from the study after day 128 for all 12 patients which is expected in mid 2022.
Amal Kakas: Before I turn the call over to Eric, I want to highlight our recently announced collaboration with FDA, NIH, and leading public and private organizations focused on gene therapy development. The Bespoke Gene Therapy Consortium is part of the NIH Accelering Medicine Partnership Program. It's focused on advancing gene therapies for ultra-rare diseases. At Ultogenics, we believe we have a responsibility to support the development of treatment for as many rare diseases as possible, including these ultra-wheres that might not otherwise get treated.
Turning to the U S. We expect to begin dosing patients under the revised protocol later this quarter the dose in U S is lower than ex U S. But the patients are restricted to the younger smaller four to eight year old age group our experience with the first five patients previously treated suggests that younger smaller patients can respond to treatment.
This dose after drug loading with four repeated low doses over three months.
For Wilson disease, we've also begun enrolling participants in the baseline evaluation phase of our pivotal study you at UX seven O. One is an AAV nine gene therapy are especially designed copper trans part of that can restore normal copper metabolism and distribution.
Amal Kakas: We also believe that this joint collaboration will help identify ways to improve the development process and create a further improved regulatory paradigm to improve the efficiency and effectiveness of the development of the next generation of gene therapies for all rare diseases. With that, I'll turn the call now over to Eric.
The design of our novel Phase <unk> study in Wilson disease is notable because.
It enables a seamless transition from a traditional dose finding phase one two study right into a pivotal study, which will save time.
Eric Harris: Thank you, Emo, and good afternoon, everyone. The commercial and field teams continue to operate in the North and Latin American regions despite the ongoing pandemic.
I don't know if this is our fourth clinical stage gene therapy program in our first targeting a more prevalent genetic disease.
Neal will provide more information on this program and study later on in her section.
Eric Harris: This has led to another strong quarter, building on the significant momentum that we generated.
Also of note is that the U S 701 program for Wilson disease is our second program do you use the ultrasonics producer cell line or P. C. L gene therapy manufacturing system.
Eric Harris: generated in the first half of the year. In the press release we issued earlier today,
Eric Harris: We further highlighted this by guiding towards the upper end of the 180 to $190 range for 2021 Krista Revenue and Ultritori. This would represent greater than a 35% year-over-year growth.
All technologies and novel approach similar to vaccine manufacturing.
Designed to yield a more productive and consistent AAV production process.
The result is that we are manufacturing commercial grade material at commercial scale for the first clinical patients with a substantial reduction in costs compared with triple transfection processes.
Eric Harris: Within the North American region, we continue to
This process allows us to manufacture enough material to treat all the patients randomized to <unk> 701 in the phase one two portion of the study with a single run.
Eric Harris: see steady underlying demand from both the pediatric and adult markets as the total number of prescribers
Eric Harris: of prescribers surpassed 1,
Significantly driving down Cogs and important element when thinking about the potential reimbursement challenges in the future for gene therapy products.
Eric Harris: The split of the pediatric and adult patients remains approximately 50-50, while the total number of patients on therapy continues to increase. As Amo mentioned earlier, we expect this split will continue to shift towards a greater portion of adults on Preseda. As the number of teams continues to increase
We are continuing to invest in our PCL system. Most recently as part of our preclinical AAV program for Duchenne muscular dystrophy, we expect the greater productivity productivity of the PCL system.
Eric Harris: focus on finding doctors who have adult patients with XLH or TIO dispersed in the community setting. Compliance remains very high, in part because of the ultracare patient support services team because patients who begin therapy recognize how much better they can feel when on Prisita.
Will be especially important for more common and higher dose indications like Duchenne the mountain cost the product can be an important factor.
Moving to the rest of our clinical pipeline, we are advancing four additional programs that further demonstrate the diversity of our portfolio across modalities.
Eric Harris: Outside of the U.S., the man for Chris Vita continues to gain momentum, third-quarter revenue in Latin America increased significantly versus the second quarter, partly reflecting the uneven ordering patterns we expect within that region. However, if you compare the revenue of the first three quarters in 2021 versus the same time period in 2020,
All four of these programs have new studies starting over the next few months and three of these studies will be pivotal.
Our gene therapy for <unk> hundred one for GSD, one a and D. T X 301 for OTC deficiency are both moving into phase III studies based on durable positive phase two results over multiple years of follow up.
We're also on track to initiate a pivotal phase two three study of our newest program U S $1 43.
Eric Harris: You can begin to see the significant opportunity ahead of us.
This monoclonal antibody will be tested in pediatric and adult patients with osteogenesis imperfecta.
Eric Harris: Revenue over that time period grew by approximately 115%.
Larger rare genetic bone diseases complements the capabilities, we've developed with Chris Vita.
Eric Harris: percent driven by increasing underlying demand.
Wrapping up with our commercial programs. Despite the recent challenges of the Covid cover Delta variant. Our team has continued to be affected that is supporting compliance for patients already receiving our therapies.
Eric Harris: This is the result of all the work the teams have been doing for the last couple of years to educate healthcare providers, find patients, and work with regulatory and reimbursement
As well as increasing new patient starts across all products.
Eric Harris: We are in the final stages of negotiating full reimbursement with the Brazilian authorities, and in the meantime, we continue to receive orders from the Ministry of Health to support patients.
With Chris Vita.
The successful launch continues and we are now tracking towards the upper end of our full year guidance.
Adult patients are an increasing portion of patients we are identifying and converting to treatment.
Eric Harris: have been granted an injunction to receive this therapy. Turning now to DeJote, which was approved for the treatment of long-changed fatty acid observation disorders or LCFAOV by the FDA in the middle of 2020 and by Health Canada earlier this year.
In Latin America, Christy to continues to do especially well revenue in that region has more than doubled year to date in 2021 versus 2020. This growth is backed by increases across the board in patient identification patients who have a prescription and are navigating reimbursement process and patients receiving reimbursed therapy.
Eric Harris: Canada earlier this year. In the third quarter, we added approximately 40 star forms, bringing the total since launch to approximately
We are nearing the conclusion of the formal reimbursement process in Brazil for access to the product, which should help further growth there.
Eric Harris: Approximately 310 stars
Eric Harris: As of the end of the quarter, this has resulted in approximately 250 patients being reimbursed therapy.
With <unk>, we're continuing to build the momentum of a strong lunch all the key metrics show. The teams are able to find patients and quickly get them on reimbursed therapy.
Eric Harris: approximately 145 unique healthcare for
Eric Harris: Health care providers have written prescriptions for Jogi, and we are continuing to see growth in the number who have written multiple prescriptions.
We are near 10% of the expected population of L. C. F O D patients now being prescribed <unk> in the first year or so of launch.
Eric Harris: Much of the success we have seen in the first year of launch is driven by a couple of factors. First, the strong demand for Jovey as a major center to treat inborn errors and metabolism. Second, our patient support services team is doing a great job.
Those are always are also growing in Europe, driven by significant increases in named patient requests in France and other countries in the region.
Before I turn the call over to Eric I wanted to highlight our recently announced collaboration with F. D. A NIH and leading public and private organizations focused on gene therapy development.
It'd be spoke gene therapy consortium as part of the NIH accelerating medicines partnership program is focused on advancing gene therapies for ultra rare diseases.
Eric Harris: Patients and their families as they navigate the insurance process and work through any issues they might
Eric Harris: They might have and receive them.
Ajay Ultrashape, we believe we have responsibility to support the development of treatment for many rare diseases possible, including these ultra whereas that might not otherwise get treated. We also believe that this joint collaboration will help identify ways to improve the development process and create a further improved regulatory paradigm to improve efficiency.
Eric Harris: Over time, we believe the market for dodovi will continue to grow at a
Eric Harris: steady pace similar to other products in the space. Outside of the U.S., uptake of the JOLB remains strong through our name, patient, early access programs. In Europe, JOLDi is growing driven by steady increases in main patient requests.
Eric Harris: Request in France.
Thickness of the development of the next generation of gene therapies for all rare diseases.
Eric Harris: We are continuing to work with regional regulators to gain full approval to treat all patients who could benefit from Zogovic. In fact, the Brazilian National Health Surveillance Agency,
With that I'll turn the call now over to Eric.
Thank you Guillermo and good afternoon, everyone. The commercial and field teams continue to execute in the north and Latin American regions.
Eric Harris: The agency recently approved the Jogi for the treatment of both pediatric and adult patients with LCFAOD.
The ongoing pandemic.
This has led to another strong quarter building on significant momentum that was generated in the first half of the year.
Eric Harris: As it's typical within that country, we are now working with the Ministry of Finance to get full reimbursement.
The press release, we issued earlier today.
We further highlighted by guiding towards the upper end of the $180 million to $190 million range for 2021 Cristina revenue.
Eric Harris: These are important steps forward.
Eric Harris: as we seek to provide broad access to Jovey and the Latin American League. As the teams look to close out the year, they will continue to adapt to the ever-changing COVID landscape so that patients can continue to benefit from our
Ultra again ex territories, this would represent greater than 35% year over year growth.
Within the North American region, we continue to see steady underlying demand from both the pediatric and.
Adult markets as total number of prescribers surpassed 1000.
Eric Harris: to benefit from our product. With that, I'll turn the call over to them to share the financial results.
The split of the pediatric and adult patients remaining approximately 50 50, while the total number of patients on therapy continues to increase.
Maurice Thomas Raycroft: Thanks; we issued a press release earlier today that included a financial statement.
As Emil mentioned earlier, we expect the split will continue shifting.
Maurice Thomas Raycroft: That included a financial update, which I will briefly summarize. Company revenue for the quarter ending September 30th, 2021, totaled 81.6 million. Crispita revenue in Ultrigenics territories grew to 50.3 million, including 43 million from the North American profit share territory and net product sales of 7.4 million in other regions. Total royalty revenue related to the sales of Krispita in the European territory was 4. The Jolvie revenue for the quarter was 10.7 million. As we have stated before, we will not be providing guidance for DeJolvi in these first quarters of launch.
Towards a greater portion of adult Christina.
Has it changed since Q2.
Increased focus on finding doctors, who have adult patients with X L a or CIL disbursed in the community setting.
Compliance remains very high in part because of the auto care of patient support services team and because patients who began therapy recognize how much better they can feel went on Christina.
Outside of the U S demand for Christina continues to gain momentum third.
Third quarter revenue in Latin America.
<unk> grew significantly versus the second quarter, partly reflecting the uneven ordering patterns, we expect within that region. However.
However, if you compare the revenue.
The first three quarters in 2021 versus the same period time period. In 2020, you can begin to see the significant opportunity ahead of us.
Maurice Thomas Raycroft: We believe the metrics Eric just discussed better describe the success we are seeing so far. Mepsevi revenue for the third quarter of 2021 was 3.9 million, and we expect these revenues may modestly increase over time. Third quarter 2021 revenue also includes 12.1 million related to the tech transfer as part of our strategic manufacturing partnership with Daichi Sankyo around our PCL and HEC2-23 technologies. As we have discussed previously in the fourth quarter, the revenue we recognize from this agreement will taper significantly as the tech transfer activities wind down as planned. Additional details on this revenue recognition can be found in our annual and quarterly reports filed with the SEC.
Revenue over that time period grew approximately 115% driven by increasing underlying demand.
This is the result of the work the teams have been doing for the last couple of years educating health care providers.
Patience and work with regulatory and reimbursement authorities.
We are in the final stages of negotiating all reimbursement with the Brazilian authorities and in the meantime continue to receive orders from the Ministry of health to support patients who have been granted an injunction to receive this therapy.
Turning now to <unk>, which was approved for the treatment of long chain fatty acid oxidation disorders, or LC <unk> by the FDA in the middle of 2020, when by Health, Canada earlier this year.
In the third quarter, we added approximately 40 stock loans, bringing the total since launch to approximately 310, sorry forums.
Maurice Thomas Raycroft: Total operating expenses for the quarter were 171, which included research and development expenses of 113.4 million. SGNA expenses are at 53.9 million and cost of sales of 4.2 million. We continue to expect our R&D cost to increase in 2021 compared to 2020 as we support three pivotal gene therapy clinical trials, the UX143, a Phase 23 clinical study in osteogenesis in Perfecta, and the Phase 122 study for our most advanced MRNA program, UX 053 in GSD3, and a number of other preclinical activities as we We also expect SGNA to modestly increase in 2021 as we continue to support the expansion of the launches of Crospita, De Jovi, and Sevi.
As of the end of the quarter. This has resulted in approximately 250 patients on reimbursed therapy.
Approximately 145 unique health care providers have written a prescription for the job and we are continuing to see growth in the number who have written multiple prescriptions.
Much of the success, we are seeing in the FERC up launch was driven by a couple of factors first the strong demand for this type of major centers put in born errors of metabolism.
Second our patient support services team is doing a great job supporting patients and their families as they navigate the insurance process.
Work through any issues they might have received the jewelry.
Overtime, we believe demand for the Adobe will continue to grow at a steady pace similar to other products in this space.
Outside of the U S uptake of video viewing remains strong through our named patient and early access programs in Europe, because Europe is growing driven by steady increases in named patient requests in fragrance.
Maurice Thomas Raycroft: For the quarter ended September 30th, 2010, the net loss was $73 million or $1. This compares to a net loss for the same period in 2020 of $68.8 million or $1.13 per share. The net loss for the third quarter, 2021, includes a $25.7 million increase in the fair value of investments and equity securities as compared to an 11.5 million decrease in Q3 2020. Net cash use in operations for the nine months ended September 30th, 2021, was $284.4 million compared to $69.8 million for the same period in 2020.
We are continuing to work with regional regulatory regulators to gain full approval to treat all patients who could benefit from the Dolby and fac.
The Brazilian National Health Surveillance Agency recently approved <unk> for the treatment of both pediatric and adult patients with LC <unk>.
As is typical with them that constantly we are now working with the ministry of finance.
Full reimbursement approval.
These are important steps forward as we seek to provide broad access to the Dolby in the Latin American regrouped.
As the teams look to close out the year, we will continue to adapt to the ever changing Colgate landscape. So ensure that patients continue to benefit from our products.
Maurice Thomas Raycroft: Net cash use in the nine months ended September 30th, 2021 includes the $50 million upfront payment for the closing of the Moreo License and Collaboration Agreement, compared to the net cash used in the same period of 2020, that included $154 million of operating cash received from Daiichi Sanquio related to the collaboration and license agreements. We ended the third quarter with approximately $941 million in cash, cash equivalents, and marketable securities. This puts us in a strong capital position to reach key clinical and commercial milestones as we continue executing our development and commercial strategies. Now, I'll let Camille touch on some of our clinical programs. Camille?
With that I'll turn the call over to Marty to share the financial results.
Thanks, Eric.
You correctly earlier today that included a financial update which I will briefly summarize company revenue for the quarter ending September 30th 2000, Twenty's mine totaled 81.6 million Christy that revenue in ultra Genex territory grew to $53 million, including 40 point 43 million from the.
North American profit share territory, and net product sales of seven 4 million in other regions.
Total royalty revenue related to the sale of the crispy that in the European territory.
<unk> 7 million.
Agility revenue for the quarter was $10 7 million as we have stated before we will not be providing guidance for <unk> in the first quarters of launch we believe the metrics Eric just discussed better describes the success we are seeing so far.
Camille L. Bedrosian: Thank you, Marty, and I too wish everyone a good afternoon. Before I share updates from our ongoing clinical programs, I'd like to review new data that were presented last month at the International Network for Fatty Acid Oxidation Research.
Next Debbie revenue for the third quarter of 2021 with $2 9 million and we expect these revenues may modestly increase overtime.
Camille L. Bedrosian: or inform 2021 virtual conference. The results represent data over a longer period of time.
Third quarter 2021 revenue also includes 12 point 12.1 million related to the tech transfer as part of our strategic manufacturing partnership with Daiichi Sankyo around our PCL and Heck 293 technologies.
Camille L. Bedrosian: and on additional patients in an independent group of patients with long-chain fatty acid oxidation disorders, LCFOD, treated with Dov in an extension study. There was a statistically significant reduction in annualized major clinical events or MCEs and annualized duration of these events in 33%
As we have discussed previously and in the fourth quarter 2021. The revenue we recognized from the agreement will taper significantly as the tech transfer activities wind down as planned.
Camille L. Bedrosian: 33 patients who had not previously received treatment with Dolderob when comparing the 18 months prior to treatment to the median 21.9 months on therapy.
Additional details on this revenue recognition can be found in our annual and quarterly reports filed with the SEC.
Total operating expenses for the quarter were 171 5 million, which includes research and development expenses.
Camille L. Bedrosian: In these patients, the median annualized rate of MCEs went from 2.00 to 0.8 per year, or an 86% reduction, P value 0.0343, and the median annualized duration of MCEs went from 8.66 to 0.8 days, or a 91% reduction, p-value 0. These data are consistent with the previous published results. Next, I'll shift to GTX 102, the antisense ologonucleotide, ASO, that we are developing in partnership with genetics for the treatment of Angelman syndrome. Angelman is a severe neurodolm
Expenses of $113 4 million SG&A expenses at $53 9 million in cost of sales of $4 2 million.
We continue to expect our R&D cost to increase in 2021 compared to 2020 and at least the part three pivotal gene therapy clinical trials that you ask one for three phase three clinical study in Genesis and protect that and the phase one two study for our most advanced mrna program <unk> 053 <unk>.
Camille L. Bedrosian: neurogenetic disorder that affects approximately 60 in the developed world.
Great and a number about their preclinical activities as they get ready to advance the next programs into the clinic.
Camille L. Bedrosian: We, with our partner genetics, are currently enrolling the Phase 1-study in Canada and the UK. Dosing at the Canadian site has already begun, with the UK to follow shortly. As a reminder, initially, two patients in the under eight-year-old cohort and two in the over eight-year-old cohort will be enrolled. Following each patient's second monthly dose and the completion of a two-week follow-up period, a data monitoring committee will review the available safety data to determine if they recommend moving forward with enrolling the remaining four patients in each age cohort.
We also expect SG&A to modestly increase in 2021 as they compare as it continued to support the expansion of the lunch at the crispy does to Joe Bae and savvy.
For the quarter ended September 32021, net loss was 73 million or $1 eight per share. This compares to a net loss for the same period in 2020, and $68 8 million or $1 13 per share.
The net loss for the third quarter 2021 includes the $25 7 million increase in the fair value of investments and equity securities as compared to 11 million 11 5 million decrease in Q3 2020.
Camille L. Bedrosian: Following extensive discussions with the FDA, we were able to reach agreement on a modified protocol that will allow us to dose naive patients younger than eight years old in the United States. The revised protocol will enroll a patient, split between a GTX-2 treatment arm and a comparator group, with the active group receiving 2.
Net cash used in operations for the nine months ended September 32021, with $284 4 million compared to $69 8 million for the same period in 2020 net cash used in the nine months ended September 32021 at $50 million upfront payment for the closing of the morale.
Camille L. Bedrosian: monthly doses for four months. The comparator group can then eventually enter the same dosing regimen. Because the dose level is lower in the U.
Camille L. Bedrosian: We have narrowed enrollment to the younger patient group of 4 to 8 years old. The site in the U.S. has a number of patients identified who are all eager to participate in the study. We expect dosing to begin later this quarter. I'll now turn to our three pivotal gene therapy programs, starting with UX701 for the treatment of Wilson disease. Wilson disease is a rare genetic disorder of copper metabolism due to a mutation in the ATP7B or copper transporter gene. This results in the accumulation of copper in the liver and brain, particularly a potentially progressive serious disease. We estimate there are approximately
License and collaboration agreement compared to the net cash used in the same period of 2020 that included $154 million.
Operating cash received from Daiichi Sankyo was related to the collaboration and license agreement.
We ended the third quarter with approximately $941 million in cash cash equivalence and marketable securities disposed that puts us in a strong capital position to reach key clinical and commercial milestones as they continue executing our development and commercial strategy.
Camille L. Bedrosian: 50,000 patients in the developed world who have Wilson disease. Last month, we announced that we have successfully screened the first patients in the seamless phase one, two, three study that aims to
So now I'll, let Camille touch on some of our clinical programs Camille.
Thank you Marty and I too wish everyone a good afternoon.
Camille L. Bedrosian: to directly address the mutated ATP-B gene. These patients are now in a six to 12-based-evaluation period, where they will be evaluated to ensure stable measures of disease, such as 20-12-year-old
Before I share updates from our ongoing clinical programs I'd like to review new data that were presented last month at the international network for fatty acid oxidation research and management or inform 2021 virtual conference.
Camille L. Bedrosian: Such as 24-hour urinary copper concentration, complete blood count, and liver function test.
The results represent data over a longer period of time and an additional patient and an independent group of patients with long chain fatty acid oxidation disorders, <unk> treated with they'll Jovi, an extension study.
Camille L. Bedrosian: Following this baseline screening period, patients will be randomized to
Camille L. Bedrosian: Patients will be randomized and treated with UX701 or placebo.
There was a statistically significant reduction in annualized major clinical events, our MCT ease and annualized duration of these events for 33 patients who had not previously received treatment with don't tell the when comparing the 18 months prior to treatment to the media and 21 nine months on <unk>.
Camille L. Bedrosian: Next, DTX401 for the treatment of glycogen storage disease type 1A or GSD1A is a disease that arises from a defect in the glucose 6 phosphatase enzyme, which is essential to the liver's ability to release glucose into the blood, and its deficiency leads to serious hypoglycemia. GSD1A is the most common genetically inherited glycogen storage disease with an estimated 6,000 patients in the developed We have a number of sites already activated and expect the first patients from the U.S. Canadian sites to enter the 4-8-week baseline evaluation period around the end of the year.
Arabi.
And these patients the median annualized rate of Mtge's went from 2.00 to 0.28 per year or an 86% reduction P values are 0.0343.
And the median annualized duration of MCT. He's went from $8 6620, 0.8 days or 91% reduction P value of 0.03 to five.
Camille L. Bedrosian: During this period, patients will be monitored to establish four consecutive weeks of clinically stable disease through the use of a controlled diet, oral glucose replacement therapy, and a continuous glucose monitor. Following this baseline evaluation period, patients will be randomized and treated with either DTX 401 or placebo. Our third pivotal gene therapy is DTX301 for the treatment of or or otc deficiency.
These data are consistent with the previous published results.
Next I'll shift to Gtx 102, anti sense oligonucleotide ASO that we are developing with part in partnership with kinetics for the treatment of Angelman syndrome.
Angelman is a severe neuro genetic disorder that affects approximately 60000 patients in the developed world.
We with our partner genetics are currently enrolling the phase one two study in Canada and the U K.
Camille L. Bedrosian: OTC is a critical component of the
Dosing at the Canadians site has already begun with the U K to follow shortly.
Camille L. Bedrosian: component of the urea cycle that metabolizes toxic ammonia into urea that can then be safely excreted in the
As a reminder, initially to patients in the under eight year old and two in the over eight year old cohort will be enrolled.
Camille L. Bedrosian: Ammonium is a very potent neurotoxic compound and can lead to coma, serious brain injury, and death. There are approximately 10,000 patients in the developed world, 80% being late onset. We currently expect the first patients to enter the four to eight-baseline evaluation period,
Following each patient second monthly dose and the completion of a two week follow up period.
Data monitoring Committee will review the available safety data to determine if they recommend moving forward with them rolling the remaining four patients in each age cohort.
Camille L. Bedrosian: During this period, patients will be monitored to establish four weeks of clinically and metabolically stable disease through a protein-restricted diet and or the use of an ammonia scavenger. Following this baseline evaluation period, patients will be randomized and treated with either DTX 301 or placebo.
Following extensive discussions with the FDA, we were able to reach agreement on a modified protocol that will allow us to dose naive patients younger than eight years old in the United States.
The revised protocol the umbrella a patients split between a gtx 102 treatment arm and a comparator group with the active group receiving two milligrams monthly doses for four months.
Camille L. Bedrosian: The last program I will touch on is UX143 for the
Camille L. Bedrosian: of osteogenesis or osteogenesis, or OI. OI is a large genetic bone disorder with approximately 60,000 patients in the developed world, and most of our XLH doctors have many more patients with OI than with XLH. These patients have reduced or abnormal collagen that triggers a maladaptive bone remodeling response.
The comparator group can then eventually enter the same dosing regimen.
Because the dose level is lower than the U S protocol, we have narrowed enrollment to the younger age patient group of four to eight years old.
The site in the U S has a number of patients identified who are all eager to participate in the study.
We expect dosing to begin later this quarter.
I'll now turn to our three pivotal gene therapy programs, starting with <unk> 701 for the treatment of Wilson disease.
Camille L. Bedrosian: The body recognizes the bad collagen and breaks down bone in a repeated cycling attempt to fix the issue. However, patients with OI are unable to create normal collagen, and that then leads to an over-resorption and inadequate net production of bone, and the bone weakness creates the risk for fracture. What we have found in animal models is that if you stimulate the production of more bone with antiskaroftin or other agents, you can improve bone strength to normal or near normal, even while the collagen is still mutated.
Wilson disease is a rare genetic disorder of copper metabolism due to a mutation in the ATP 70, our copper transporter gene.
This results in the accumulation of copper in the liver and brain, particularly and potentially progressive serious disease.
We estimate there are approximately 50000 patients in the developed world who have Wilson disease.
Last month, we announced that we have successfully screened the first patients in the seamless phase <unk> study that aims to directly address the mutated ATP 70 gene.
Camille L. Bedrosian: This would suggest that the fragility of the bone is not due to the collagen but is actually the body's maladaptor response to this. UX-143 or Situamad is a fully human antiskarostomonochon antibody that should help the body right this imbalance by stimulating bone production and suppressing bone resorption, restoring the net balance toward bone production. Moreo's asteroid study showed a dose-dependent increase in P1NP and a decrease in CTX serum levels, supporting this hypothesis.
These patients are now in a six to 12 week baseline evaluation period, where they will be evaluated to ensure stable measures of disease, such as 24 hour urinary copper concentration complete blood count and liver function tests.
Following this baseline screening period patients will be randomized and treated with <unk> 701 or placebo.
Next <unk> 401 for the treatment of glycogen storage disease type, one a or GSD. One a is a disease that arises from a defect in the glucose six phosphatase or <unk> enzyme, which is essential to the livers ability to release glucose to the bloodstream and its efficiency.
Camille L. Bedrosian: There were also continuous improvements in bone mineral density over the 12-month treatment period of the study, including an 8 to 10% improvement in the spinal column, which is a better anabolic result than other commonly used bone anabolic agents. In the pivotal, two, and three study we expect to initiate later this year, we'll study pediatric and young adult patients ranging from 5 to 25 years old, with and without a history of prior Bifascanate treatment.
Leads to serious hypoglycemia.
GSD <unk> is the most common genetically inherited glycogen storage disease with an estimated 6000 patients in the developed world.
We have a number of sites already activated and expect the first patients from the U S and Canadian sites to enter the four to eight week baseline evaluation period around the end of the year.
Camille L. Bedrosian: The first part of this study will enroll approximately 40 patients.
During this period patients will be monitored to established four consecutive weeks of clinically stable disease through the use of a controlled diet.
Camille L. Bedrosian: and we'll evaluate a few doses compared to placebo.
Camille L. Bedrosian: Once a dose is identified, the study will enroll additional patients at the optimal dose.
Oral glucose replacement therapy, and a continuous glucose monitoring.
Followed this baseline evaluation period patients will be randomized and treated with either <unk> or placebo.
Camille L. Bedrosian: will enroll additional patients at the optimal dose level. We will provide more details on the study design and endpoints when we initiate the study later this year. With this update, I will now turn back the call to AML. Thank you, Camille.
Our third pivotal gene therapy is <unk> 301 for the treatment of ornithine <unk> or OTC deficiency.
OTC is a critical component of the urea cycle that metabolize as toxic ammonia into urea that can then be safely excreted in the urine.
Amal Kakas: Before we close out, I'd like to provide a quick reminder of the key upcoming milestones for the company. For GTX 102 in Angerman Syndrome, we have dosed patients in Canada and will dose patients in the UK and US later this quarter. We plan to provide a preliminary update on this program around the end of the year. For our gene therapy pipeline, we're continuing to enroll the UX701 Phase 123 study for Wilson. We'll share longer-term follow-up phase one-two data at ICIEM from the studies of DTX 401 in GST1 and DTX301 in OTC.
Ammonia is a very potent neurotoxin compound and can lead to coma.
Serious brain injury and death.
There are approximately 10000 patients in the developed world with 80% being late onset.
We currently expect the first patients to enter the four to eight week baseline evaluation period around the end of the year.
During this period patients will be monitored to established four weeks of clinically and metabolically stable disease through a protein restricted diet and or they used as ammonia scavengers.
Following this baseline evaluation period patients will be randomized and treated with either <unk> or placebo.
The last program I will touch on is <unk> 143 for the treatment of osteogenesis Imperfecta R O I.
Amal Kakas: We will initiate face-stides in both these programs around the end of 2021. For UX-143 and Ostegenus Imperfecta, we'll initiate the pivotal phase 2-3 study in pediatric patients around the end of the year, with studies in other age groups anticipated to begin next year. As you can see, our clinical pipeline is one of the largest and most diverse in the rare disease space and targets a number of genetic diseases with significant unmet needs.
O I has a large genetic bone disorder with approximately 60000 patients in the developed world and most of our XL H doctors have many more patients with Oi than X L. H.
These patients have reduced or abnormal collagen it triggers a maladaptive bone remodeling response.
The body recognizes the back collagen and breaks down bone and a repeat of cycling attempt to fix the issue.
However, patients with Hawaii are unable to create normal collagen and that then leads to an over resorption and inadequate net production of bone and the bone weakness creates the risk for fractures.
Amal Kakas: With four Piddle studies enrolling in early 2022 and the Asianman program back up and running, we look forward to updating you on our progress. With that, let's move on to your questions. Operator. Please provide the Q&A instructions.
What we have found in animal models is that if you stimulate the production of more bone with anti scar often or other agents you can improve the bone strength to normal or near normal even while the collagen is still mutated.
This would suggest that the facility of the bond is not due to the collagen, but it's actually the body's maladaptive response to this defect.
UX 143, or if the tourism that is a fully human anti <unk> monoclonal antibody that should help the body right. This imbalance by stimulating bone production and suppressing bone resorption.
Operator: Thank you. To ask a question, you may press Star 1 on your telephone keypad. If you would like to withdraw your question, you may press the pound key. We'll pause for just a moment to compile the Q&A roster.
Restoring the net balance to our bone production.
Mario's asteroid study showed a dose dependent increase in <unk> and a decrease in CTX serum levels supporting this hypothesis.
Operator: And our first question comes from the
There were also continuous improvements in bone mineral density over the 12 months treatment period of the study, including an 8% to 10% improvement in the spinal column, which is a better anabolic result than other commonly used bone anabolic agents.
Tazeen Ahmad: comes from the line of Desin Ahmed from Bank of America. Your line is now open.
Tazeen Ahmad: Okay, thank you guys. Good evening, and thanks for taking my questions. Two quick ones, Amel.
The pivotal two three study we expect to initiate later this year.
Tazeen Ahmad: For gene therapy for DMD, where do you think that there is the most room to differentiate from what could potentially be on the market? So, for example, the latest updates, it seems like Surrepta and Pfizer.
We will study pediatric and young adult patients ranging from five to 25 years old with and without a history of prior bisphosphonate treatment.
The first part of the study will enroll approximately 40 patients and will evaluate a few doses compared to placebo.
Tazeen Ahmad: and Pfizer are now both expecting their phase three data for
Tazeen Ahmad: for their programs in the early part of 2023. Obviously, we don't know what they would look like, but let's say that they're both on the market before then.
Once the dose is identified the study will enroll additional patients at the optimal dose level.
We will provide more details on the study design and endpoints when we initiate the study later this year.
Tazeen Ahmad: your program, where do you see the biggest opportunity there? And then quickly, for the 7-
With this update I will now turn back the call to Emil Thank.
Tazeen Ahmad: Program Are you able to tell us what you expect the screen rate to be for the AV9 antibodies with patients that you're looking to enroll into the study? Sure, look, on the DMD program, we know when we started, we were well behind the two program leaders, Sirepta and Pfizer, and so our goal is to come up with a better combination of microdestrofen and vector, along with the manufacturing process we think will be superior, to do some other things.
Thank you Camille.
Before we close out I would like to provide a quick reminder of the key upcoming milestones for the company.
For Gtx 102 in Angelman syndrome, we've dosed patients in Canada will dose patients in the U K and U S. Later this quarter, we plan to provide a preliminary update on this program around the end of the year.
For our gene therapy pipeline will continue enrolling the UX 701 phase three study for Wilson will share longer term follow up.
Amal Kakas: to do some other improvements related to how we administer the drug, which we think can enhance delivery. So the combination of factors, I think, will help us provide an improvement. Now, our ability to look at development and improve the quality of the development strategy and the endpoints and evaluations, I think they're another factor. You know, we think all the microsrophins do work, and I think there's room for further improvement, and we have that opportunity as a fast follower.
As <unk> two data at the ICA I am from the studies of <unk> hundred one in GSD, one and <unk> 301 in OTC.
We will initiate phase II studies in both of these program around the end of 2021.
For you, it's 143 and <unk> Jensen perfect.
Initiate the pivotal phase three study in pediatric patients around the end of the year with studies in other age groups anticipated to begin next year.
As you can see our clinical pipeline as one of the largest and most diverse in the rare disease space.
Amal Kakas: But we're well behind, and we have a lot of work cut out for us, so we appreciate both companies or the other companies are very capable. But we do think we have some angles on how to be superior to the other Deschen.
Target the number of genetic diseases with significant unmet need.
With four pivotal studies enrolling in early 2022, and the Angelman program back up and running we look forward to updating you on our progress.
Amal Kakas: programs. With regard to AV9 for 701, we haven't put out any information on the frequency, but we don't expect it to be an important issue with regard to being able to enroll the study and execute it. So far, multiple patients have already qualified, so we haven't seen an issue.
With that let's move on to your questions. Operator, please provide the Q&A instructions.
Thank you.
It's a question you May press star one on your telephone keypad. If you would like to withdraw. Your question you May press depend Keith we'll pause for just a moment to compile the kidney roster.
Operator: And your next question from Yaron Werbera? Your line is now open.
Yaron Benjamin Werber: Congrats everybody. All of great progress.
Yaron Benjamin Werber: Questions just really quickly on the gene therapy stuff as well, so I know, and Wilki just got up and running.
And our first question comes from the line of Pleasant Ahmed from Bank of America.
Yaron Benjamin Werber: Would we maybe be able to?
Yaron Benjamin Werber: to expect any maybe preliminary updates from phase one to next year and, if so, when you're thinking that could be, and then just for g sd one, an OTC, seems like you're expecting to start dosing patients probably realistically early next year now.
Your line is now open.
Okay. Thank you guys good evening and thanks for taking my questions.
Two quick ones Emil.
For <unk> gene therapy for DMD.
Where do you think that there is the most room to differentiate from what potentially could be in the market. So for example at the.
Yaron Benjamin Werber: I just wanted to see if there's maybe anything that's kind of limited in getting these up and running or rate of enrollment or anything like that that we should be aware of. Thanks very much.
<unk> it seems like the Raptor and Pfizer are now both expecting their phase III data.
For their programs in the early part of 2023, obviously, we don't know what they would look like but let's say that they are both on the market before.
Amal Kakas: Sure, so for the phase one to Wilson data, we expect by late in the year we should have enough data on phase one and two of that segment of the program to be able to talk about it. We can't yet commit to the exact timing of that data, but that's what we're expecting. The phase one-two data would be separately analyzed from the phase three data, so this gives us a little bit more room to maneuver with regard to disclosing what we find.
Your program, where do you see the biggest opportunity there and then quickly for the 701 program are you able to tell us what you expect the screen out rate to be for the AAV nine antibodies with patients that you are looking to enroll into the study.
Sure. So look on the DMD program, we know when we started we're well behind the two program leaders interrupted advisor and so on.
Our goal is to come up with a better.
Amal Kakas: But we expect we should know the dose and have information about it by late in the year. We expect to enroll fairly promptly for Wilson, so there are a lot of patients. We think our program is a track of the one for patients, and we've managed to work to make it as convenient as possible, so we could enhance enrollment. With regard to OTC, you know, we made the decision that GST won and Wilson was able to get going quicker.
Combination Microsoft drove in and vector.
Vector along with a manufacturing process, we think will be superior.
And.
To do some other improvements related to how we administer the drug which we think can enhance the delivery.
So the combination of factors I think will help us provide an improvement in our ability to look at development and improve the quality of the development strategy and endpoints in valuations I think are another factor.
Thank all of the micros drove in to do work on it.
I think theres room for further improvement and we have that opportunity as a fast follower, but we're well behind and we have a lot of work cut out for us. So we appreciate both companies or other companies are very capable, but we do think we have some angles on how to be superior to the other Duchenne program.
Amal Kakas: The challenge of OTCs, we had some work to do with the agency regarding the urea genesis test and the involvement of the device division of FDA, CDRH, which led to some more conversations that just took more time to get through. And right now, I would say CBER and CERH are both strapped and over-extended, and it took more time than we would have liked. So that's the main thing, really getting up and running.
With regard to a benign for 701, we haven't put out any information on the frequency, but we don't expect as being an important issue with regard to being able to enroll the study and execute so far already multiple patients have qualified so we haven't seen an issue.
Okay. Thank you.
Amal Kakas: We've been doing patient diagnosis for all of our programs with our global team and have lined up a lot of patients that we know are out there, so at least we believe we should be able to help improve the actual enrollment process once we get started. But it took a little longer to get through some of the regulatory steps for OTC. Now that those are behind us, we're ready to get going, but there is still, that's the one main difference for OTC.
And your next question from Yaron Werber from Cowen. Your line is now open.
Congrats to everybody all the great progress thanks for the question.
Just really quickly on the gene therapy stuff as well.
I know in Wilson, you, just got up and running.
We maybe be able to expect any maybe preliminary updates from the phase one two next year and if so maybe when youre thinking that could be.
Operator: Your next question from Murray Raycraft. Jeffreys, your line is not open.
And then just for an GSD one eight OTC it seems like Youre expecting to start dosing patients probably realistically early next year now so I just wanted to see if there is maybe anything of note that kind of limited getting these up and running or rate of enrollment or anything like that that we should be aware of thanks very much.
Maury Raycroft: Hi everyone, congrats on the progress, and thanks for taking my question. I was just going to check in on Angelman for the preliminary data for the four patients around year-end. Can you set expectations on what we should be focused on, how much follow-up we should expect, and will there be enough total drug administered to see some efficacy and definitive safety?
Sure so for the.
Phase one two Wilson data, we expect by late in the year, we should have.
<unk> data on the phase one to that segment of the program to be able to talk about it but we can't yet commit to the exact timing of that data.
Maury Raycroft: Yeah, I think the main thing you'll see is that we'll talk about patients' doses and, you know, what we're looking at with regard to safety at that time. It's a little bit early on in the time, of course, to know what the loading dose would be, and there was a run-in period where these patients were started, and that pushed out the amount of data we'll get.
But that's what we're expecting and the phase one two data would be separately analyzed from the phase III, So which gives us a little bit more room to maneuver with regard to disclosing what we find but.
But we expect we should know the dose and have information about it by late in the year next year.
We expect it to enroll fairly promptly for Wilson. So there are a lot of patients. We think our program is <unk>.
Amal Kakas: But it'll be a good update on where we are with regard to any safety issues and where we go. So it'll give us a sense that everything's progressing, I think, but it will. Take, we won't have a lot of efficacy information at that point in time because it's a bit early. What we are guiding to is that the 12 patients with full data coming mid-year is really kind of the place where you get a real full feel for loading, you know, six young and six old patients, maximally titrating, and well, that'll be the best assessment. Anyway, so far, it's going well, and we're pleased to get going.
<unk> of a one for patients and we manage to work to make it as convenient as possible. So we could enhance enrollment.
With regard to OTC.
We made the decision that GSD, one in Wilson, and we're able to get going quicker. The challenge of OTC is we had some work we had to do with the agency regarding the Regenesis test in.
The involvement of the device division that FDA is CRH on that which led to some more conversations with just took more time to get through and right now I would say seeber in CRH are both strapped and <unk>.
Overextending It took more time than we would've liked.
Maury Raycroft: Got it. And as a quick follow-up, will you, um,
So that's the main thing is really getting up and running we have been doing patient diagnosis for all of our programs with our global team have wind up a lot of patients that we know are out there. So at least we we believe we should be able to help improve the actual enrollment process. Once we get started but it took a little longer to get through some of the regulatory steps or OTC that behind.
Maury Raycroft: Will you provide an update on enrollment status at the year end update on where you're at with the total of 12 patients?
Maury Raycroft: Yeah, we'll talk about where we are on the program at that time.
Operator: Okay, thanks for taking my question.
Joseph Patrick Schwartz: And your next question from Joseph Schwartz of SVB, Carolina is now open. Hi, I'm Jerry Dile, and on behalf of Joe, thank you for taking our questions.
Just now we are ready to get going but there is still that's the one main difference for OTC.
Joseph Patrick Schwartz: is on Angelman. Is there any more work you can do to help the FDA get comfortable with the risk of dosing?
Amal Kakas: with the risk benefit of dozing additional anglement patients at a higher dose.
Okay, Great makes sense, thanks very much.
Your next question from Maury Raycroft of Jefferies. Your line is now open.
Joseph Patrick Schwartz: I think the FDA is being conservative in regard to the sense of safety, and I think the thing that's going to help them is getting more data on the higher dose of XUS and comfort with the administration strategy. We have confidence in it, but, you know, for them, there's not much benefit in taking any risk.
Hi, everyone. Congrats on the progress and thanks for taking my question I was just going to check in on Angelman.
The preliminary data for the four patients around year end can you set expectations on what we should be focused on how much follow up we should expect and will there be enough total drug administered to see some efficacy in determining safety has improved.
Amal Kakas: So we're able to get started at two, which will give us some information, so we restricted it because of that dose to young patients, where the amy milligrams of loaded drugs should be significant enough to give an effect based on what we saw before. But we think that the dose XUS is going to give us safety and ethics information, which we would use to revise the U.S. approval process eventually this coming year. I think clinical data is what's gonna move the needle on FDA at this point, and it's on track to get it.
Yeah, I think the main thing Youll see is that we'll talk about.
Patients dosed and what we're looking at with regard to safety at that time I, It's a little bit early on in the time course to know what the loading would be and.
There is there was a run in period, where these patients were started and that pushed out the amount of data, we will get but it'll be a good update on where we are with regard to any safety issues and where we go but I. So it'll give us a sense that everything is progressing I think but it would take we won't have a lot of efficacy information at that point in time.
Joseph Patrick Schwartz: Okay, and I guess as a follow-on to that, you kind of touched upon it, but I guess to what extent did you
It's a bit early.
What we are guiding to those at the 12 patients have full data coming mid year is really kind of the place where you'll get a real full feel for loading.
Joseph Patrick Schwartz: I think that the FDA will consider learning from your ongoing UK and Canada study where you'll be able to
Joseph Patrick Schwartz: you'll be able to dose higher. Have you had any conversations with the FDA about this?
Young and six old patients.
Maximally tight trading and well I think that'll be the best assessment.
Amal Kakas: Well, you know, I've done a lot of regulatory work; one of the things I know that doesn't really work that well is to ask some hypothetical questions because they won't commit to anything. So you can't say, if the data look good there, will you do this? They'd say, well, let's see what that says. It's not really a productive thing to ask them. But I know from history, and I can tell you I did it on four other programs, I went XUS, got more data on safety and efficacy, come back to the U.S., got their agreement, and got those products approved. All right? So I've done it four times before. I think that's probably enough evidence that that strategy can work. Okay, great, that's very helpful. And then my second question is about the Wilson program.
Anyway, so far it's going well and we're pleased to get going.
Got it and just a quick follow up.
Provide an update on enrollment status at the year end update where you're at with the total of 12 patients.
Yeah, we'll talk about where we're at and status of the program at that time.
Okay. Thanks for taking my question.
Yeah.
And your next question from Joseph Schwartz.
Of SBB Leerink. Your line is now open.
Hi, I'm Jerry dialing in for Joe. Thank you for taking my question the first one.
As an angelman is there any more work you can do to help the FDA get comfortable with the risk benefit of dosing additional angelman patients at a higher dose.
Yes, well.
I think the FDA is being.
Conservative with regard to the sense of safety and I think the thing that's going to help them is getting more data on the higher doses ex U S and comfort with the administration strategy, we have confidence in it confidence in it but.
For them, there's not much benefit in taking any risks. So we were able to get started it too which will give us some information simply that we restricted because of that dose to be the young patients where the milligrams of loaded drug should be significant enough to give an effect based on what we saw before.
Amal Kakas: I believe that DTX 701 has an inducible promoter. Curious to know how it works and how, and have you learned anything from your experience with DTX401, which also has this feature, although it's likely, you know, different, and there still needs to be patients for, and there needed to be patients who brought glucose to equilibrate over time. These were the expected outcomes.
But we think that the dose ex U S is going to give us the safety and efficacy information, which we would use to.
To revise the U S program eventually in this.
This coming year. So I think clinical data is what's going to move the needle for FDA at this point and that's on track to get it.
Amal Kakas: Do you foresee the need for any quibbling amongst Wilson patients; do you expect that they will achieve homeostasis right away to get the dose rate? Yeah, well, we're, depending on the dose to get to the right level. There isn't an inducible feature in 711 that I'm aware of. The 401...
Okay, Great and I guess as a follow on to that you've kind of touched upon it but I guess to what extent do you think that the FDA will consider learnings from your ongoing U K and Canada study, where you'll be able to dose higher.
Have you had any conversations with the FDA about about about this.
Amal Kakas: It's not just a do-it's more of a regulation that is, The 401 promoter includes all the normal signaling elements that you require to control your glucose correctly for insulin and glucose gone cortisol and other things so that our trans gene for collection and thyroid disease will respond to your body's signals, which I think is extremely important in managing glucose correctly, right? You want a system that responds. For the metal ion, I don't think there is actually a particularly need.
Well you know.
I've done a lot of regulatory and one of the things I know it doesn't really work that well to ask some hypothetical questions.
Because they won't commit to anything so you can't say if data look good there will you do this they'd say well, let's see what that says is.
It's not really a productive thing to ask them, so, but I know from our history and I can tell you I've gone on for other programs I've gone ex U S obtained more data on safety efficacy come back to the U S got their agreement and got those products approved alright, So I've done it four times before I think that's probably enough evidence that that strategy can work.
Amal Kakas: As long as you're getting enough metal transport, excess will not harm you. Basically, your body already regulates whether it's sending the copper to the bile or whether it's going to the Golgi. The Golgi is how you make serulaplasm. If you have excess, it ends up going to the bile. And so how much transport is present? It's not, I think, as critical as it might be in glucose-minute regulation. Okay, great.
Okay, Great. That's very helpful. And then my second question is on the Wilson program I believe with a D check something no. One has an inducible promoter curious to know how it works and how it and have you learned anything from your experience with <unk> 401, which also has a feature although looks like me you know just rang and they are selling.
Could be patients or and there needed to be patient.
Operator: Okay, great, thank you for the clarification. And your next question is from Gina Wong of Barclays.
Blood glucose to cobalt.
Overtime.
And of course, Stephen <unk> for any purple, that's collaborating amongst Wilson patients or do you expect that they will achieve homeostasis right away to get the dose right.
Gena Wang: Thank you for taking my questions. I also have two short questions regarding Andrewman. So, Emily, just wondering how the FDA picked the 2 milligram dose, the, you know, file process, or data to support that? And then, second question: I just wanted to confirm for the year.
Yeah, well, we're depending on the dose to get to the right level, where there isn't an inducible feature in 71 then.
That I'm aware of the 401.
It's not just to do for both more of a regulation that is.
The 401 promoter includes all of the normal.
Signaling elements that you require to control your glucose correctly for insulin and glucagon and cortisol and other things so that our transient for collections rare disease will respond to your body's signals, which I think is extremely important in managing glucose correctly right you want a system that responds.
Gena Wang: update, so will we see four patient data with each having three doses or two doses?
Gena Wang: doses or two doses. And then quickly, I think you commented a little bit, just wondering what kind of safety data in terms of, say, follow-up or dose that from XUS do you think it will allow you to dose higher in the U.S.?
For the for the metal I and I don't think there is actually a particular need as long as youre getting enough metal transport excess will not harm you.
Amal Kakas: Okay, so the 2 milligram dose is basically a level of 1 tenth of the dose at which we saw a safety problem in one patient. Remember, patient 5 had the safety problem at 20 mix, and they wanted a dose one tenth of that dose. That's the basis for that choice at 2Mig. I don't really think that 2 to 3.3 is a big difference, but they prefer to stay a full 10
Basically your body already regulates whether it's sending the copper to the bile or whether it's going to the golgi.
The goals. He is how he makes rule plasm, if you need if you have excess it ends up going to the bile and so how much transport is present as long as I think is critical as it might be in a.
Minute regulation.
Okay.
Okay, great. Thank you for the clarification.
And your next question from Gena Wang of Barclays.
Thank you for taking my questions I also have two short questions regarding and Joanne.
Amal Kakas: We decided just tactically not to try to titrate, right? They didn't tell us not to, but we just decided not to even push it because we were going to get what we needed, XUS, and it felt that it was more important just to get started and start treating some patients, and we restricted ourselves to the young patients because we felt we had a better chance of seeing efficacy in that group. And the idea is we would have a group of patients now, four patients that would run at 2-mig, and we'll have the X-U.S. patients, so two-mig that get about a total of 8, and the XUS patients will get around 16.6 mig, so we'll actually essentially have like the equivalent of sort of a half of the dose cohort.
And I'm just wondering how did the FTE pay the two milligram dose.
The thought process or data.
To support that and then second question is just wanted to confirm for the year and upbeat. So will we see for patient data with each of three doses or two doses and then quickly I think of you comment a little bit just wondering you know what kind of safety data in terms of.
As a follow up or does that from ex U S. Do you think it will allow you to do is higher in the U S.
Yes.
Okay. So the two milligram dose is basically a level, it's 110th of the dose at which we saw in one patient safety problem remember patient five had the safety problem at 20, Megs and they wanted to have more dose 110th of that dose that's the basis for that choice to make.
Amal Kakas: So if you look at the totality of this, it'll give us the potential for looking at dose response combining U.S. and X-U.S. data. So there is a plus side to it, and we think it's just about getting started in the U.S. The FDA just wants to be conservative and protect patients, and we're willing to work with them and get through that and get on to the next step.
I don't really think that two to three three is a big difference, but they preferred to stay full 10 tax below.
We decided just tactically not to try to titrate alright, they didn't tell us not to but we just decided not to even push it because.
Operator: And we're comfortable that the dose administration change we're making and how we're managing dose XUS will be successful, and therefore, we'll be able to bring that to the U.S. The end of the year update, we will have some safety data through the first two to three doses, but I think right now it won't, it's not going to be a very complete update.
We're going to get what we needed ex U S and it felt to US more important just to get started and started treating some dose some patients and we restricted to the young patients because we felt we had a better chance of seeing efficacy in that group and the idea is we would have a group of patients now.
For patients that would run at two Meg and we will have ex U S. Patients. So two makes it get about a total of eight in the ex U S patients will get around $16 six Mig so well actually essentially have like.
Karri Kasimut: It'll be some dosing; you'll get a sense of whether patients are having symptoms, but we won't have to be able to fully load the patients. We had hoped to have more like three to four doses, but it's more like two to three, and the update, I think, will give people comfort. If we're showing safety, then we'll at least understand that we can dose this level and not get the problem. And to get to efficacy, though, we think you need several doses in order to get there.
The equivalent of a sort of a half of the dose.
Cohort. So if you look at totality of this it will give us the potential for looking at dose response, combining U S and ex U S. Data. So there is a plus side to it and we think it's just about getting started in the U S and the.
The FDA just wanted to be conservative and protect patients and we're willing to work with them and get through that and get onto the next step and we're comfortable that dose administration change, we're making in our managing dose ex U S will be successful and therefore, it will be able to bring that to the U S. At the end of the year update we've been.
Karri Kasimut: So the efficacy will be, you know, we'll provide what we have, but it will be more important to think, look forward to the full data set on 12 patients mid-year, which will be, I think, a truly substantial amount of information on what's going on with that ALGO at the doses and loads that we are proposing. The last item, you said safety data, XUS.
We will have some safety data and.
Through the first few.
Two to three doses, but I think right now it won't it's not going to be a very complete update there will be some dosing you'll get a sense of whether patients are having the symptoms, but we want to build a fully loaded the patients. We had hoped to have more like three to four doses, but it's more like two to three.
Karri Kasimut: I think the type of safety that we'll be able to show them is that we're not seeing the exacerbation of protein into the CSF that we had seen, and the fact that we're not seeing lower extremity weakness clinically, as well as using the neurological assessments. And, of course, if we saw a problem, we would do an MRI scan. So, but assuming we haven't seen anything, it's the combination of the laboratory and clinical findings that we'll be able to use in terms of justifying what we would do in the U.S.
And the update I think we'll give people comfort should if if we're showing safety than we will at least understand that we can dose at this level and not get the problem and to get loaded the efficacy that we think you need several doses in order to get there so the efficacy will be.
We'll provide what we have but it will be more important I think to look forward to the.
Karri Kasimut: But we'd expect to take the data from the majority of patients in the U.S., and after we've gotten our four doses loaded in those U.S., put that package together, and come back to FDA, in order for the next cohort that we would initiate to begin at a dosing plan that would be more optimal for achieving
The full data set on 12 patients mid year, which will be I think a truly substantial amount of information on what's going on with that I'll go with.
At the dosing and load that we're proposing.
And the last item you said safety data ex U S.
I think the type of safety will be able to show them is that we're not seeing the.
Exacerbation of protein into the CSF that we had seen.
Karri Kasimut: And the next question is from Karri Kasimut of JPM Morgan. Your line is now open.
And the fact that we're not seeing lower extremity weakness via both clinically as well as easing the neurological.
Karri Kasimut: Great, this is Tom on behalf of Corey. Thanks for taking the question. I guess maybe just a quick one on Citrusaumab or EX-143. I know you guys haven't laid out the whole design of the Phase 23 study there, but I'm curious if you can just comment on what specifically you'll be looking for in the Phase 2 portion to make a decision on Go Forward Dose. And then I was also curious if we should be expecting a day.
<unk> and of course, if we saw a problem we would do an MRI scan so but assuming we haven't seen anything it's the combination of.
The laboratory and clinical findings that we'll be able to use.
In terms of justifying what we would do in the U S. But we would expect to take the data from the majority of patients in the U S and after we've gotten our four doses loaded in those U S patients.
To put that package together come back the FDA in order for the next.
Amal Kakas: I'm expecting a data update from the phase two portion that's slightly more specific. Thank you. Sure, so the phase two portion will focus on P1MP, which
Cohort.
And that we would initiate.
To begin at a dosing and dosing plan that would be more.
Optimal for achieving efficacy.
Great. Thank you.
Amal Kakas: Sure, so the phase two portion will focus on P1M, which is the synthetic peptides that are released when your body is making collagen and laying down new bone. So it's an early sign of new bone creation.
And the next question from Carl Kirst from that of Jpmorgan. Your line is now open.
Great. This is Thomas on for Cory. Thanks for taking my question I guess, maybe just a quick one on the chosen Niobrara X 133 and <unk>.
You guys haven't laid out the whole design of the phase III study there, but curious if you can just comment on what.
Amal Kakas: And we'll rely on that, we have seen it before, as a dose response. We'll be looking at 20 and a higher dose, and what we're trying to do is figure out for the children whether a higher dose might work better. And so it's not only just, it's not which dose, it's the dose range, and, and, what you're trying to do is, and, and, what you're trying to do is, and, and, and, you're trying to do it.
Specifically, you'll be looking for in the phase two portion to make a decision on a go forward dose.
And then also curious if we should be expecting a data update from the phase two portion of that slightly specifically thank you.
Sure. So the phase II portion will focus on <unk>, which is the.
Synthetic peptides that were released when your body is making collagen and laying down new bone. So its the early sign of newborn creation and will rely on that we have seen it before I provided a dose response will be looking at 'twenty and a higher dose and that's what we're trying to figure out for the children, whether a higher dose might work.
Amal Kakas: Age for dosing that we'll figure out; we'll use a couple of doses in the first group of patients that are in phase one, two parts to make the decision and then define a dosing algorithm for children up to adults that we would use then in the pivotal study. We know the 20 mig per kilo dose provides a substantial improvement in bone roll density already in hand. So we have a strong anchor for what's an effective dose.
Better and so it's not only just thought which doses to dose range and age for dosing that we'll figure out we use a couple of dosing in the first group of patients that are in the phase one two strategic partnerships to make the decision and then define a dosing algorithm for children up to adults.
Amal Kakas: So this is just about making sure we do the best we can for the children and that we optimize and assure that there isn't more efficacy that we would have missed out on by not increasing the dose either for children or adolescents or older patients. So that's the basic idea. With that, we will move into the rolling phase 3 patients and use the dosing algorithm to find
That we would use in the pivotal study we know the 20 Meg per kilo dose provides a substantial improvement in bone mineral density already in hand, So we have a strong anchor for what's an effective dose.
So this is just about making sure we do the best we can for the children and that we optimize and assure that there isn't more efficacy that we would have.
Operator: Hey, good evening, and thank you for taking our question. This is Elizabeth from Salveen. Just wanted to ask, and I might have missed it, but are you looking to start redosing patients that were originally treated in Engelman's program? And, I guess, when could that happen?
Missed out on by not increasing the dose either for children or adolescents are older patients. So that's the basic idea with that we'll move into the rolling the phase III patients and.
Salveen Jaswal Richter: We have not reached agreement on redoing those patients. The FDA agency wants us to treat these other patients and do a little more work to figure out whether we can demonstrate it's safe to redose those patients. We believe it's safe, the problems have resolved fully, and we do not think there is any immunological type of basis for what's going on.
At the using the dosing algorithm defined.
Okay. Thank you.
Yeah.
Next question from solving rich curious Goldman Sachs.
Hey, good evening, guys and thank you for taking our question. This is Elizabeth on first olivine.
Just wanted to ask and I could have missed it but are you looking to start dosing patients that were originally treated.
Amal Kakas: But right now, we have not received a plan to redose those five patients, but we will work on that. But our first step, we think, is getting patients dosed and treated safely. With that in hand, then you can also go back and talk about redoing those initial patients. They're anxious to get started, but we have to work through this first step of treating some naive patients before we can make that move. Great, thank you.
And the Engelman This program and I guess when could that happen.
We have not yet reached agreement on re dosing those patients.
If the agency wants us to treat these other patients and do a little more work to figure out whether we can demonstrate that safe to re doses patients.
We believe its safe that problems have resolved fully and we do not think there is any hematological type.
Operator: Next question from Yigo Natty Group: My name is now open.
Basis for what's going on but right now we have not received a plan to re dose those five patients but.
Yigal Dov Nochomovitz: injection volume was playing a role in the observed muscle weakness, assuming it's not volume related. Was this perhaps a sequence-dependent effect based on the UVE3A sequence or just the result of any antics oligens in the CNA? Yeah, so volume is not really a factor. We've been using 10 cc, and in some cases, they got more 15 cc, but it really didn't relate to the volume of the artificial CSF being used, so we don't think volume is a factor at all.
We will work on that but our first step we think is getting patients dosed in treated safely with that in hand. Then you can also go back and talk about re dosing. Those initial patients there were anxious to get started.
But we have to work through this first step of treating some naive patients before we can make that move.
Great. Thank you.
Next question from Yigal <unk> of Citigroup.
It is now open.
Hi, Thank you very much for taking my questions and congrats on the progress I just had a quick one on Haynesville then could you tell us what the volume of the two milligram doses and have you ruled out that injection volume.
Amal Kakas: We do think, though, that in these patients, since they were relatively active patients, they wouldn't lay down, and they stood up quickly, that the drug tended to settle down the bottom of their cord, which we think was probably a factor in incubating their nerve roots in a much higher concentration of drugs. Now, we don't think it's sequence specific. Everything we've done would suggest it's not.
Playing a role and he observed muscle weakness and assuming it's not volume related.
This perhaps.
Pendant effects based on the <unk> three a sequence or just the result of any antisense oligos president and CFO.
Yes, so volume is not really a factor we've been yeah.
Using.
Amal Kakas: We think it's a high concentration effect. Even with sequence specific, we would have seen the phenomenon up and down the spinal cord because the clinical effect happening in the brain demonstrates the sequence is there. But yeah, we don't see the problem.
<unk> in some cases, they've got more than <unk>.
But it really didn't relate to the volume of the artificial CSF being used. So you don't think volume is a factor at all.
We do think though that.
That in these patients that they were there since they were relatively active patients they wouldn't lay down and they stood up quickly the drug tended to settle down the bottom of their cord, which we think was probably a factor in in incubating their nerve roots and a much higher concentration of drug.
Amal Kakas: The drug and the colleague were originally heavily screen for sequence-dependent effects, and the screen negative, and toxicologically was negative. So we don't think it's a sequence-specific effect at all.
Amal Kakas: I think it's non-specific, and at this point, my best sense is that this is more of a chemical irritation effect of the oligo present at high concentrations and kids that don't lay down. In the UK and Canada now, we're sedating them longer, keeping them laying down in Trindellenberg, and to make sure the drug is moving forward or also adding a flush. That's just to keep the drug moving and make sure it mixes rather than settles in at the bottom of their spines. So that's what we think at the moment, and we don't think it's sequence or volume-dependent.
Now we don't think its sequence specific everything we've done would suggest its not we think it's a high concentration effect. If it was seeking specific we would've seen that phenomenon and up and up and down the spinal cord because the clinical effect happening in the brain demonstrates that the sequence is there, but yeah, we don't see the problem.
The drug in the colleague was originally heavily screened for sequence dependent effects and screen negative in toxicology really was negative. So we don't think it's sequence specific fact at all thing it's nonspecific.
Amal Kakas: I got it, thank you, and then just a separate question on petruzumab. Could you just comment on why you believe an antipsloroscan antibody would be a better approach in osteogenesis imperfecta as opposed to one of the commercially available grant gallant antibodies? Well, the rank-all stuff like denosemap, the data weren't that great.
And at this point.
My best sense is that this is more of a.
Chemical irritation effect of the I'll go president of high concentrations in kids that don't lay down.
In the U K, and Canada, an hour today, and even longer keeping them laying down and turn dalenberg and to make sure. The drug is moving forward. We're also adding a flush that's just to keep the drug moving and make sure it mixes and rather than settling in at the bottom of the spine.
Operator: The truth is they're blocking resorption more, but the drill deficiency is in anabolism, making bone. The final difference in blocking resorption is that you are also inhibiting the overall turnover of bone in the correct way, that is, resorving bone that's not needed and making new bone that is needed. When you look at what's happening in these patients, they're not making enough new bone. Their bones are essentially osteoporic; they're not making enough, they're resorbing too much, not making enough new bone.
So that's what we think at the moment and we don't think it's sequence are volume dependent.
Okay got it thanks, and then just a separate question on <unk>.
Could you just comment on why you believe that MTS fluoroscopy antibody would be a better approach and osteogenesis imperfecta as opposed to one of the commercially available ramp antibody.
Well the rank all stuff like Denosumab. The data were not that great. The truth is they're blocking resort option more but the drill deficiencies in antibody anabolism, making bone.
Final difference in blocking resort <unk> is that you are also inhibiting the overall turnover of bone in the correct way that is resolving them as needed and making new bone that is needed. When you look at what's happening in these patients, they're not making enough new bone their bonds are essentially off the product theyre, not making enough, they're resorbing too much not making enough new boat.
Operator: So you really want an anabolic agent, and the animalic agents, the reason that it's important is that they're activating normal mechanisms in your bone. And where the bone gets laid down will be driven by where the signals are for building weakness. So when you have bone movement, there is a mechanism to detect that weakness and movement and recruit the osteoblast to make osseides and make new bone. So the whole mechanism is designed to fill in bone where it's weakest, and in animal models, this particular mechanism can result in normalizing bone strength within a few weeks of treatment in a model with defective collagen.
So you really want an anabolic agent and the anabolic agents. The reason it's important is that there are activating normal mechanisms in your bone and where the Boeing is laid down will be driven by where the signals are for billing weakness.
So when you have bone movement, there is a mechanism biological maxim to detect that weakness and movement and recruit the osteoblasts to make off decided to make new bone. So the whole mechanism is designed to fill inbound where its weakest.
Operator: So it is a potential fundamental impact on bone, and it's why we've been guiding people away from the idea that the weakness of bone in OI is due to the collagen, but rather it's due to the maladaptive response primarily, and that adaptive response causes bones to be resorbed too much and not enough bone to be made. And so sclerosin is the right biological signal to turn on bone production, and it has some anti-resorcephive effects too, but it's primarily an anabolic agent.
And in animal models. This this particular mechanism can result in normalizing bone strength within a few weeks of treatment and a model with defective collagen. So it is a potential fundamental impact on bone and it's why we've been guiding people away the idea that the weakness of bone and Oi is due to the collagen but.
Rather it's due to the maladaptive response, primarily.
And that that adapter response causes bone to be resolved too much and not enough bone to be made and so suraj. The right biological signaled a turn on bone production and it have some anti resort of effects too, but it's primarily an anabolic agent. We think could have a profound effect on oi and we think of all of the mechanisms out there. We think this is the.
Operator: We think it could have a profound effect on OI, and of all the mechanisms out there, we think this is the strongest one because it derives osteoblast recruitment and production of new bone, both of which are being effective or alive.
Strongest one because it drives osteoblast treatment and production of new bone.
Joon So Lee: Your next question from Julie F. Your line is now open.
Amal Kakas: All right, thanks for the updates on the question. Can you provide any more granularity on the patient disposition from the first three cohorts? Is the lack of urgency by the FDA to allow redosing based on some continued maintenance of XC, or is there something else? Can I have a follow-up?
Both are being effective for a while.
Great. Thank you.
Your next question from Jay Li <unk>. Your line is now open.
Alright, thanks for the update on the questions can you provide any more granularity granularity on the patient disposition from the first three cohorts is a lack of urgency by the FDA to allow re dosing based on from continued maintenance opex fee or is there something else.
Amal Kakas: Well, there's no lack of urgency. We've been urgently working to get those patients retreated since last November, so if anything, it's fear and frustration for us because it should have happened. I think the agency is, we've provided all the data we have which show that there really is no mechanism other than a local irritation contact kind of injury. However, we have, in their minds definitely proven that, and so there is a question about what is going on. But based on what we see, there's definitely evidence.
Follow up.
Well, there's no lack of urgency and urgently working and getting those patients retreated as his last November so if anything it's in.
Your frustration for us because it should have happened.
The agency is we've provided all the data we have would show.
There really is no mechanism other than a local irritation contact kind of injury.
And.
However, we have in their mind definitely proven that and so there was a question what is going on.
Amal Kakas: Redosing is something we'd like to start doing, but I don't think at this point it's the right step forward for the agency. I think we should treat some patients with low doses, show we can do it safely, show we're getting efficacy, and then re-approach them with the concept of redosing. I think showing that we can get this done safely will help us move forward on redos. But fortunately, it didn't happen right away.
But based on what we see there is that's the only evidence re dosing.
We'd like to start doing but I don't think at this point is the right step forward for the agency I think we treat some patients with low doses show, we can do it safely show, we're getting efficacy and then re approached them with the concept of re dosing.
I think showing that we can get this done safely will help us.
Move forward on re dosing.
But fortunately, but didn't happen right away.
Amal Kakas: Are the patients continuing to maintain some efficacy, or have they gone back to the base?
The patients continue to maintain for efficacy or have they gone back to baseline.
Amal Kakas: Well, they did, you know, they maintained their improvements for four or five months. Most of them have moved toward baseline in some ways, but I've heard from the PI that, in fact, some of the patients have retained long term some of the benefits they obtained during the treatment period. So it is possible that once the neurons have communicated and trained, they can actually maintain some of the signaling and improvement. So that's encouraging, so they're not all the way back to baseline for some of the features, but clearly, they're not as good as they were when they were on Doug.
Well they did.
They maintain their improvements for four or five months and.
Most of them have moved toward baseline.
In some ways, but I have heard from the pie that in fact, some of the patients have retained long term some of the benefits. They obtained during the treatment period. So it is possible that once the neurons have communicated and training that they can actually maintain some of the signaling an improvement so that's encouraging because they're not all the way back to base.
For some of the features but clearly they are not as good as they were when they were on Doug.
Joon So Lee: Okay, and then the second question is, do you have any plans to vectorize GTS?
Okay.
And the second question is do you have any plans to vector gtx, one or two looks like Jim Wilson is working with faster develop bacterize micro RNA targeting the same <unk> create etfs.
Amal Kakas: It's one or two, you know; it looks like Jim Wilson is working with FAST to develop vectorized microRNA.
Amal Kakas: Targeting the same UB3ATS and the
Amal Kakas: There's another company using Vectaray, Short Hair, Target, and same. So I was just curious about your long-term plans.
There is another company using vector I shorthair or any target I would say.
So just curious your all your long term plans I know, it's not it's not them, it's a tricky Lucas.
Amal Kakas: I mean, it's not a tricky locus.
Amal Kakas: Well, TRECELOCUS, and when you do it, vectorize, it's totally unregulated. So the challenge right now, and we're doing gene therapy in the brain, we are working on CKL5 deficiency, and we have a lot of work to do on it. What I can tell you, though, is the reliability of getting all the neurons treated efficiently consistently is tougher with gene therapy. You end up with some neurons with a lot of expression, and it's important to get enough expression in all and not too much in some. And so, and keep in mind that the only imprinted cells are the neurons, not the other cells. So there are some complexities to how this would work.
Well, it's tricky locus and when you do it vector is it's totally unregulated. So the challenge right now and we're doing gene therapy in the brain. We are working on <unk> deficiency, and we have a lot of work on it but I can tell you, though is the reliability of getting all the neurons treated efficiently consistently it's tougher with gene therapy.
End up with some new Orleans with a lot of expression and it's important to get enough expression in all and not too much in some.
So and keep in mind that the only imprinted cells of the neurons not the other cells. So.
So there is some complexity as to how this would work well you don't know that the efficiency of gene therapy in the brain and it's going to be good enough for.
Amal Kakas: We don't know that the efficiency of gene therapy in the brain is going to be good enough for in terms of what fraction of neurons are truly transformed. And so I would actually say that ASO strategies are more likely to treat more neurons consistently and will be more effective, and that there's still work to be done. I know everyone wants to vectorize and try to do that, but let's see how many of them get there where they actually are reliably controlling that in wide-arive neurons in a consistent way. The brain is tricky.
Angelman in terms of how what fraction neurons are truly transformed.
So I would actually say that the sales strategies are more likely to treat more neurons consistently and will be more effective and that there is still work to be done and everyone wants to vector is and try to do that but.
How many of them gotten there where they actually are a reliably controlling that in a wide variety of neurons in a consistent way. The brain is tricky I think DSO strategy. We're using is going to provide a more consistent result.
Amal Kakas: I think the ASO strategy we're using is going to provide a more consistent result going forward, but with time, there's no question. With time, could there be a gene therapy? At that point, we hope to be in a position to do it ourselves. Right now, we're very excited about the potential of an ASO that can bring benefits and help establish standards for what you can expect by turning on paternal UB3A.
Going forward in <unk>.
With time, there's no question with time could there be a gene therapy, yes at.
At that point, we will hope to be in position to be able to do it ourselves, but right. Now we're very excited about potential of an ASO that can bring benefit and help establish standards. What you can expect by turning on paternal <unk>.
Thanks.
Operator: Your next question from Degon Ha of Stissel. Your line is
Your next question from Doug and Heart of Stifel. Your line is now open.
Dae Gon Ha: Good evening, thanks for taking our questions. Just two from me as well, going back to Angelman.
Good evening, Thanks for taking our questions just two from me as well go.
Going back to Angelman. So first on the U K and Canada protocol given that it includes the trend dalenberg as well as the artificial CSF flush.
Dae Gon Ha: So first, the UK and Canada protocols, given that it includes the Trindelenberg as well as the artificial CSF flush. I guess we're mostly concerned about safety on the inflammation side of the question, but I was just wondering, would the artificial CSF flush in a way kind of truncate how soon you can actually see the efficacy signal and perhaps even at lower doses than what you might have seen in the first U.S. trial?
I guess, we're mostly concerned about safety from the inflammation side of the question, but I was just wondering what the artificial CSF flush in a way kind of truncate. How soon you can actually see the efficacy signal and perhaps even at lower doses than what you might have seen in the first U S trial.
Dae Gon Ha: And then, second question related to Angelman, as we think about the U.S. trial, I know it's flat dosing, but it also doesn't include artificial CSF flushed nor the Trindelenberg. So when we think about the spinal canal, any reason to believe that, you know, compared to the 3.3, that any kind of efficacy that could emanate from these accumulated doses would be somewhat weaker than the UK Thank you.
And then second question related to Angelman as we think about the U S trial I know, it's flat dosing, but it also doesn't include artificial CSF flushed, nor the trend ellenberg.
So when we think about the spinal canal any reason to believe that.
Compared to the $3 three that any kind of efficacy that could emanate from these accumulated dose would be somewhat weaker than the U K, where the Canadian patients. Thank you.
Dae Gon Ha: Yeah, so the Trondolmurg and flush will enhance delivery to the brain, and we know this is true, and it's been true for other drugs, by the way, even chemo drugs. By doing Trindal and Mugn, you will enhance brain concentration, so that's kind of not new. That's like three decades old.
Yeah, so the Delaware and flush will enhance delivery to the brain and we know this is true and it's been true for other drugs by the way even chemo drugs by doing Janella Mergen flush you will enhance brand concentration. So that's kind of not new that's like three decades old. So it's not a unusual thing what's happening basically as you are enhancing the mix.
Amal Kakas: So it's not an unusual thing. What you're doing, basically, is you're enhancing mixing, and the artificial stuff will not reduce, it will reduce the local concentration, but it just enhances mixing so that the drug doesn't sit at high concentrations down in the lumber area. but gets mixed into the body and the volume of CSF and keeps the concentration down, the lower, the better. So it's about enhancing, it's about limiting lower concentration, but it's about mixing. Once you mix them, the brain delivery will be improved. In the U.S., we're doing a lower dose. We're maintaining the original protocol in terms of patients laying down. We're not doing Trindon-Berg and flush.
<unk> and <unk>.
Artificial stuff will not reduce it will reduce the local concentration, but it just enhances mixing so if the drug doesn't fit at high concentration is down in the lumbar area, but gets mixed into the body and volume of CSF.
And keeps the concentration down to the lower better so it's about enhancing its about limiting lower concentration, but it's about getting mixing once you mix the brain delivery will be improved in the U S. We're doing a lower dosing, where we're maintaining the original protocol in terms of patients laying down we're not doing turndown Limburg and flush.
Dae Gon Ha: It could reduce the delivery of drugs. I think we'll still get drug delivery, but I would say it's not going to be. It's not going to matter. Fundamentally, the drivers for choosing administration efficacy will come from our ex-US program. The U.S. patients will have a chance to see some efficacy, and my hope would be that we bring all that data together, and the U.S. patients and the ex-U.S. patients will get synchronized on a development strategy for dose and administration going forward next year. Got it. Thank you very much.
And.
It could reduce the delivery of drug.
Think we will get still drug delivery, but I would say, it's not going to be.
It's not going to matter and fundamentally the drivers for choice choosing where administration because it will come from our ex U S program. The U S patients will have a chance to see some efficacy and my hope would be we bring all that data together in the U S patients ex U S patients will get synchronized on our developments on a treatment strategy for dose and administration going for.
Forward in next year.
Got it thank you very much.
Operator: Your next question from Jeff Hong and Morgan Stanley.
Yeah.
Your next question from Jeff.
Morgan Stanley.
Jeff Hung: Thanks for taking the questions. Last quarter, you hadn't seen any impact from the Delta variant on identifying new patients for
Thanks for taking the questions last quarter, you said you hadn't seen any impact from Delta Varian on identifying new patients for Chris Vita <unk> did you see any impacts on identifying patients and if so do you believe that the main impact from Delta variant is behind us.
Jeff Hung: patients for Chris Vita. In 3Q, did you see any impact on identifying patients? And if so, do you believe that the main impact of the Delta variant is behind us?
Jeff Hung: Well, I don't know if we've ever said that COVID didn't have any impact on patients, I guess. It certainly had more of it last year, for sure, and it started easing up early in the year.
Well I don't know if we've ever said that COVID-19 didn't have any impact on page things. It certainly had more of it last year for sure and it got started easing up early in the year. The Delta probably had some impact in the year, but we feel like things are picking up and we're in pretty good shape in terms of how many patients we've diagnosed.
Jeff Hung: The Delta probably had some impact on the ear, but we feel like things are picking up, and we're in pretty good shape in terms of how many patients we've diagnosed and in filling the pipe. But we see things as picking up again, and so Delta probably had some impact on our ability to do face-to-face patient diagnosis and find work. But right now, we don't see that as our biggest barrier, but things are improved. Okay, and then for UX701, you said that you might not be able to treat all 50,000 patients in the developed world. What do you need to see in your studies to be clinically
Most N and filling the pipe, but we see things is picking up again, and so delta probably had some impact on our ability to do face to face patient diagnosis and find work.
But right now we don't see that as our biggest barrier, but things are improving.
Okay. Thanks, and then for <unk> 701, you said that you might not be able to treat all 50000 patients in the developed world.
What do you need to senior studies to be clinically meaningful and then I guess at that level, what proportion of the 50000 patients do you think would be addressable.
Jeff Hung: to be clinically meaningful, and I guess at that level, what proportion of the 50,000 patients do you think would be addressable? What I've said is that
Yeah, what I've said is that right.
Operator: I advise people not to include in their model that we would treat every known patient with Wilson disease with gene therapy. I don't think that's rational, think you're going to end up finding the most urgently addressed patients, so those with continuing problems, difficulties with progression of their symptoms, and it's a fraction of them, and we've said it could be, you know, a fraction, like half of them or something, but we don't really know what the number is, and I would, right now, wouldn't want to speculate.
Advice people not to include in their model that we would treat every known patient with Wilson disease gene therapy, I don't think that's rational I think youre going to end up finding.
The most urgent addressed patients or those with continuing problems difficulty complying.
Progression of their symptoms and it's a fraction of them and we've said it could be.
You know a fractionally half of them or something but we don't really know what the number is and I would right now wouldn't want to speculate I think it's going to depend on what does the efficacy really look like how powerful is it in the various types of and severity Wilson disease patients.
Operator: I think it can depend on what the efficacy really looks like, how powerful it is in the various types and severity of Wilson's disease patients. If the restoration of copper distribution has a bigger impact on neurologic function than we know today, that could change the outcome of how many patients get on therapy. But I've told people the biggest early responders would be the ones who are still having problems, even on chelators, or unable to tolerate them.
If there were duration of copper distribution has a bigger impact on neurologic function than than we know today that could change that.
The outcome of how many patients get on therapy, but I've told people. The biggest early addressable patients would be the ones that are still having problems even on key layers or unable to tolerate them and I think that would be true for almost any of the gene therapies that that's going to really be dependent on people who are needing improvement.
Operator: And I think that would be true for almost any of the gene therapies. It's going to really be dependent on people who are needing improvement to justify it. And I just think we shouldn't model assuming a huge fraction of all these patients are going to get treated. I don't think it's rational. But we do think there's a really significant fraction of those patients. I believe that restoring copper distribution will be more important than people realize today.
To justify it and I just think we shouldn't model assuming a huge fraction of all of these patients are going to get treated I don't think it's rational, but we do think there's a really significant fraction of those patients.
I'm believes that we're storing copper distribution will be more important than people realize today.
Esther Rahavala: Your next question is from Esther Rahavale of UBS.
Thank you.
Yes.
Your next question from S true Zelda UBS.
Esther Rahavala: Hi, thanks for taking my question; I apologize for asking things we've already covered. I've been jumping between calls. But on DeJolvi, can you comment on the sequential changes in the new start forms versus the total number of patients treated? When I kind of look at the sequential numbers, it looks like the start forms seem to be pretty stable quarter over quarter, but there's variability in changes in the total number of patients treated.
Hi, Thanks for taking my question I apologize, if I'm asking things you've already covered.
Jumping between calls, but did show me can you comment on the sequential changes and then you start forms versus the total treated patients.
I kind of look at the sequential numbers it looks like the stock farm seem to be pretty stable quarter over quarter.
Variability on changes in the total number of patients treated so any color you can share on that would be helpful. And then I have a quick follow up on Gtx, one I can.
Esther Rahavala: So any color you can share on that would be helpful. And then I have a quick follow-up on GtX-10. Yeah.
Eric Harris: Yeah, Eric, are you available? Do you want to talk about that particular topic?
Yeah. Eric are you available do you want to talk about that particular topic.
Eric Harris: Sure, first and foremost, I think it's important to note that the team has done a remarkable job launching this product in the midst of the pandemic.
Sure I mean first and foremost I think it's important to note that the team has done a remarkable job launching this product.
With the pandemic.
Eric Harris: You know, we see steady growth in all the key metrics, Starforms.
See steady growth in all the key metrics start forms.
Eric Harris: reimburse patients and the total number of patients
Reimburse patients in.
Total number of patients as well.
Eric Harris: The total number of patients is just another number of prescribers that have multiple prescriptions.
Number of prescribers that are.
I have multiple prescriptions. So we believe these are the best indicators.
Eric Harris: We've already stated, and the other thing I think is important to note in the first year of launch, we have about 10% of the estimated prevalent population on reimbursed treatment. We always stated as we moved into 2021 through 2020, we expected a steady gradual increase in revenue, continue consistent with other products, and I think that's what you're seeing is a steady gradual growth as we move forward.
We've already stated.
And the other thing I think is important to note in the first year of launch.
We have about 10% of the estimated permanent population on reimbursed treatment.
We've stated as we move into 2021 through 24 months, we expect a steady gradual build.
Consistent with other products and I think that's what you're seeing is.
Steady gradual growth as we move forward.
Eric Harris: Eric, I think she's speaking of the, there is a slight lag in reimbursed patients in Q3, but I think this was in the summer Delta variant. It was probably impacting some things.
Eric I think she is speaking of the there's a slight lag in the reimbursed patients from the Q3, but I think this was in the summer Delta variant it was probably.
Eric Harris: Yeah, if you look at that, those patients are just working.
Some of that thing.
Yeah, everybody can look at that.
Those patients are just working themselves through the reimbursement process and.
Eric Harris: themselves through the reimbursement process, and we fully expect them to
Eric Harris: we fully expect them to be able to transition on to treatment as reimbursement remains strong.
We fully expect them to be able to transition on to treatment is.
<unk> remained strong.
Eric Harris: Access. We've had the same pattern during Chris Fida, where we have more to start forms kind of continuing and reimbursement a little lagging, then catching up again. And I don't think there's anything there. I think the key thing to start forms is growing, and reimbursement totals are growing. So we feel good about it, strength and continued progress in the launch.
Access.
We've had the same pattern during chriss feeder, where we have more to star forms kind of continuing and reimbursement a little lagging them catching up again and I don't think Theres anything there I think the key thing start forms is growing and reimbursement totals are growing so we feel good about the strength and continued progress in the launch.
Esther Rahavala: And what is the average durability? I know it's early days in the launch, but are you sort of seeing patients sticking through therapy for the course of the year, or another way to ask is, what is the dropout rate?
Got it and what is the average durability I know it's early days in launch, but are you sort of seeing patients sticking to therapy for the course of the year or I guess or another way to ask it what is the drop off rate.
Eric Harris: We have, I think we've been seeing people staying on therapy. In fact, we have people that have been on the drug for almost 20 years now, steadily. In our trials, we lost a few people at the very beginning, but when we learned how to adapt and use dietitians to help guide people how to get started, we've generally seen people stay on the drug for very long periods of time. I don't know, I don't think we've put out specific numbers yet at this point, Eric, but... No, we haven't. Persistent, yeah. It's been to do so.
We I think we've been seeing people stay on therapy. In fact, we have people who have been on the drug almost 20 years now steadily so.
In our trials, we lost a few people at the very beginning but when we learned how to adapt and Dieticians to help guide people how to get started.
We've generally seen people stay on drug very long periods of time I don't know I don't think we put out specific numbers yet at this point, Eric but no we haven't but we havent put us.
Yes.
Ben.
Consistent yeah.
Got it and then on <unk>.
Esther Rahavala: Got it. And then on GTX 1022, can you clarify whether all four patients have already been dosed?
100 <unk>.
Can you clarify whether all four patients have already been dosed in Canada or when would that be completed.
Esther Rahavala: have already been dosed in Canada, or when would that be completed? We haven't said.
We haven't said we have we have.
Amal Kakas: multiple patients dose, and the process is ongoing. We'd expect to have All patients have got, all four patients would have gotten doses and more than one dose. But we'll put out more information at the end of the year, exact timing. It just depends on what happens at each center. But it's going along well, and we're happy with the number of patients are queued up ready to go.
Multiple patients dosed and the process is ongoing so we would expect to have.
All patients have got all four patients would've gotten dosing and more than one dose.
But we will put out more information at the end of the year exact timing. It just depends on what happens with each center, but it's going along well and we're happy with the number of patients that are queued up ready to go.
Got it thank you.
Operator: Again, to ask a question, you may press store 1 on your telephone keypad. And your last question from Joel Bidre.
Again to ask a question you May press star one on your telephone keypad.
And your last question from Joel Beatty of Baird.
Joel Lawrence Beatty: Hey, thanks for taking a question.
Your line is now open.
Hey, Thanks for taking my question could you tell us more about the manufacturing runs youre getting with the TCR gene therapy system.
Joel Lawrence Beatty: more about the manufacturing runs you're getting with the PCL, Gene Therapy
Joel Lawrence Beatty: In particular, quantifying the size of the runs as well.
In particular quantifying the size of the runs as well as the percent of scripts Youre, saying.
Joel Lawrence Beatty: runs as well as the percent of the company steps that you're seeing. Yeah, the PCL system runs at a 2,000-scale scale, all right, and disposal 2, bioreactors. And depending on the particular PCL clone, we're usually in the 60 to 80% full range fault compared to empty ones. And so it's a lot higher than you would see with triple transaction methods. That's the raw product, and then you go through purification.
Yeah, the the PCL system runs at a 2000 liter scale.
Alright, and disposal 2000 liter bioreactors and depending on the particular PCL clone where in the.
Usually in the 60% to 80% full range.
Fault compared to empties.
And so it's a lot higher than you would see with triple transfection methods. That's the raw product and then you would go through purification.
Joshua Higa: And that's concluded our Gany session. I would like to turn it back to Josh Wahiga for his final remark.
Yeah.
Great. Thank you.
And that's good that Kenny session I would now like to turn it back to Josh <unk> for final remarks.
Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at IRGenics. Thank you for joining us.
Thank you. This concludes today's call. If there are any additional questions. Please contact us by phone IR Ultra Genex dot com. Thank you for joining us.