Q3 2019 Earnings Call

Ladies we will conduct a question answer session and instructions will follow that same if anyone should you parse it states during the conference piece pastimes, they really need Touchstone tell the story as a reminder, this conference call is being recorded I would now like attuned to countries over Q host if they need.

Operator: Later, we will conduct a question and answer session, and instructions will follow at that time. If anyone should require assistance during the conference, please press star then zero on your touchstone telephone.

Operator: As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Ms. Danielle Kittley. You may begin. Thank you and good afternoon, and welcome to the Ultragenyx Pharmaceutical Financial Results and Corporate Update conference call for the third quarter of 2019. We've issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. I'm Danielle Keatley, Senior Director of Investor Relations and Corporate Communications.

You may begin.

Thank you and good afternoon, and welcome to the open Dennis Pharmaceuticals Financial result, and corporate update conference call for the third quarter 2019, we've issued a press release detailing our financial results, which you can find on our website at Ultragenyx Dotcom I'm, Danielle Keatley senior director of Investor Relations and corporate communication.

Danielle Kittley: With me today are Emil Kakkis, Chief Executive Officer and President, and Shalini Sharpe, 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 but not limited to the types of statements identified as forward-looking in our quarterly report on Form 10-Q that was filed on August 2, 2019, our quarterly report on Form 10-Q that will be filed soon, and our subsequent periodic reports filed with the SEC, which will all be available on our website in the Investor 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.

With me today or Im Okay, I guess, chief Executive Officer in President and Shalini Sharp 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 but not limited to the types of statements identified as forward looking in our quarterly report on Form 10-Q that was filed in August 2nd 2019.

Our quarterly report on Form 10-Q that will be filed soon and our subsequent periodic reports filed with the FCC, which will all be available on our website in the Investor section.

These forward looking statements represent our views only as of the data this call and involve substantial risks and uncertainties and putting money that are beyond our control.

Danielle Kittley: 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 relating to our business, see our periodic reports filed with the SEC. I'll now turn the call over to Emil. Good afternoon, everyone, and thank you for joining us.

Please note that actual results could differ materially from those projected in any forward looking statement.

For further description of the risks and uncertainties that could cause actual results could differ materially from those expressed in the forward looking statements.

As well as risks relating to our business. The CR periodic reports filed with the FCC I'll now turn the call over to handle.

Good afternoon, everyone and thank you for joining us I'll start today by discussing our commercial performance in the third quarter 2019 shown he will then summarize our financial results for the quarter well come back at the end discuss the progress across or clinical and preclinical program and our outlook for the rest of year.

Emil D. Kakkis: I'll start today by discussing our commercial performance in the third quarter of 2019. Shalini will then summarize our financial results for the quarter. I'll come back at the end to discuss the progress across our clinical and preclinical programs and our outlook for the rest of the year. Starting with Crisita, the growth we saw in the third quarter across all of our key metrics, including sales in the United States, continues to support this as one of the top rare disease launches in the industry. We have accomplished this while maintaining a responsible price for CFITA and by building a unique commercial model that places a great deal of emphasis on finding patients and helping patients and physicians through the reimbursement process. Chris V is poised to ultimately be one of the larger rare disease products worldwide.

Starting with Krissy does the growth we saw in the third quarter across all of our key metrics, including sales the United States continue to support this one of the top rare disease launches in the industry.

Accomplished while maintaining a responsible pricing could see to and by building unique commercial model, which replaces the greater emphasis on finding patients and helping patients and physicians through the reimbursement process.

Because he is poised to be ultimately be one of larger rare disease products worldwide.

Emil D. Kakkis: The execution by our U.S. commercial team in the 3rd quarter of 2019 continues to bring this important therapy to patients in need. We have seen steady quarter-on-quarter growth driven by high-level excitement and interest among patients and physicians. In the third quarter, we received approximately 170 new complete start forms, bringing the total number since launch to approximately 1,430.

Excuse me good commercial team and the third quarter 2019 continues to brings important therapy to patients in need we have seen steady quarter on quarter growth driven by high level exciting the interest.

Patient and physician.

In the third quarter, we've seen for approximately 170, new completes tarpon springs, the total number since launch to approximately 1430.

Emil D. Kakkis: The record of the split among adult and pediatric patients began to shift toward adults, with approximately 45% of adults and 55% of pediatric patients on reimbursed therapy. This compares to prior quarters where the split was 40% adult and 60% pediatric patients. We believe this increase in the proportion of adult patients will continue to grow slowly over time. Approximately 670 unique physicians have now prescribed Crisvita.

This quarter the split among adult and pediatric patients began to shift toward adults with approximately 45% adults and 55% pediatric patients on reimburse therapy. This compares to prior quarters, where the split with 40% adult and 60% pediatric patients.

We believe the increases in the proportion of adult patients will continue to grow slowly overtime.

Approximately 670 unique position as of now prescribed preceded the steady increase of 90 unique prescribers per quarter is encouraging we anticipate more prescribed for T to write second and third prescriptions are the gain experience with Chris Vito.

Emil D. Kakkis: The steady increase of 90 unique prescribers per quarter is encouraging. We anticipate more prescribers will continue to write second and third prescriptions as they gain experience with Crisvita. At the end of September, the FDA approved a label expansion for CrisV that we believe will further support our strong ongoing launch and continued penetration in the adult and pediatric markets. For adult patients, the label now includes improvement in stiffness, a meaningful measurement of muscle disease that impacts nearly all adult XLH patients. In addition, long-term sustained and further benefit in fracture healing in adults is included. For pediatric patients, the new label includes clinical data demonstrating CRIS VITA superiority versus conventional therapy from our head-to-head phase 3 study in pediatric patients. The indication has also been expanded to include infants as young as 6 months of age.

At the end of September the FDA approved a label expansion for crispy to which we believe will further support our strong ongoing launch a continued penetration in the adult and pediatric markets.

Adult patients. The label now includes a proven stiffness, a meaningful measurement of muscle disease and impacts nearly all adult XLH. Each patients. In addition, long term sustained and further benefit in fracture healing and adult is included.

For pediatric patients a new leave includes clinical data demonstrating krissy the superiority versus conventional therapy from our head to head phase three study in pediatric patients.

The indication has also been expand to crude infants as young as six months of age.

Emil D. Kakkis: This is important as we receive numerous requests for treatment at this early age and believe in the value of treating as early as possible before progressive deformity and loss of growth have occurred. In the third quarter, a steady increase of approximately 170 new patients went on reimbursed commercial therapy, bringing the total number of such patients to approximately 1,130. Our confirmatory genetic testing initiative that we commenced earlier this year is helping us to identify more patients with a confirmed diagnosis and convert those patients to reimbursed therapy. In Canada, we are encouraged by the interest and uptake among patients with private insurance in our initial year of launch. More than half of Canadians have supplemental private insurance today, a number that has grown significantly in recent years.

This is important as we received numerous requests for treatment at this earlier age I believe in the value of treating as early as possible for progressive deformity and lots of growth has occurred.

In the third quarter steady increase approximately 770, new patient went on reimbursed commercial therapy being bringing the total number of such patients to approximately 1130.

Our confirmatory genetic testing initiative that we commenced earlier this year and helping us to densify more patients with the confirmed diagnosis and convert those patients to reimburse therapy.

In Canada, we're encouraged by the interest in uptake among patients with private insurance in our initial year launch more than half the Canadians have supplemental private insurance today, a number that has grown significantly in recent years.

Emil D. Kakkis: There are already a number of pediatric and adult patients who have been approved for reimbursement and are receiving treatment through their private insurance drug plans. We also continue to pursue public reimbursement in Canada, which will take more time. Moving into Latin America, there continues to be significant interest and excitement about this treatment option. In Argentina and Colombia, the number of patients on reimbursed named patient treatment continues to increase, and the feedback has been very positive. In Brazil, we are currently in the process of getting pricing and full reimbursement approval from the Ministry of Health. The first two patients have now been treated after successfully negotiating the legal review process, and there are more patients currently undergoing the process. Ultimately, we believe there is significant potential for casein in Latin America with growing demand in multiple countries for the product.

Already a number of pediatric and adult patients who have been approved for reimbursed in our receiving proceeds through their private insurance drug plan.

We also continue to pursue public reimbursement tenant, which will take more time.

Moving to Latin America, there continues to be significant interest and excitement about this treatment option.

Argentina, Colombia, the number of patients are reimbursed named patient treatment continues to increase and the feedback has been very positive.

In Brazil, we're currently in the process of getting pricing at full reimbursement clean from an astute from the Ministry of health. The first two patients have now been treated after successfully negotiating legal review process and there are more patients currently now being the process.

Ultimately, we believe there was a significant because the fees in Latin America with growing demand in multiple countries for the product.

Earlier today, our partner Cheryl Karen announced that the European but this is agency has accepted their application for the expanded use of proceeds for adults with Exelate in Europe . This applications now being reviewed we're pleased to the step forward to bring this therapy to more patients in Europe .

Emil D. Kakkis: Earlier today, our partner Carol Kirin announced that the European Medicines Agency has accepted their application for the expanded use of CRISPR-Vita for adults with exhalation urope. This application is now being reviewed, and we are pleased with the step forward to bring this therapy to more patients in Europe. Turning to MepCevi, this therapy is approved in the United States, Europe, and Brazil, and the demand continues to build gradually. This is typical for enzyme replacement therapies.

Briefly turning that savvy therapies approved the United States Europe in Brazil, and the demand continues to build gradually as is typical for enzyme replacement therapy.

Shalini Sharpe: We're also continuing reimbursement discussions with various government health authorities throughout the world. With that, I'll turn the call over to Shalini, who will provide a financial update. Thank you, Emil, and good afternoon, everyone. Earlier today, we issued a press release that included a financial update, which I will briefly summarize. Total Ultragenyx revenue for the three months ending September 30, 2019 was $25.8 million. Chris Vita Sales in North America, Europe, and Latin America, which are shared with our partner Kiowa Kirin, or KKC, were approximately $81 million for the third quarter and approximately $211 million year-to-date. Total CrisVita revenue recognized by Ultragenyx for the three months ending September 30, 2019, was $22.6 million. This includes $19.5 million in collaboration revenue in the North American Profit Share Territory, $2 million in royalty revenue on KKC sales in the European Territory, and $1.1 million in net product revenue in other regions. In the United States, a significant order was placed on the last day of the quarter, which will not be recognized as revenue until the fourth quarter due to shipping terms.

We're also continuing reimbursement discussions various gotten health authority throughout the world.

With that I'll turn the call Shelley, who will provide financial update.

Thank you able and good afternoon, everyone earlier today, we issued a press release that included a financial update which I will briefly summarize.

Total ultragenyx revenue for the three months ending September Thirtyth Twain 19 with $25.8 million.

Chris Mena sales in North America, Europe , and Latin America, which are shared with our partner Kyowa Kirin or take Casey were approximately $81 million for the third quarter and approximately $211 million year to date.

Total crispy their revenue recognized ultragenyx for the three months ending September Thirtyth 2019.

Was $22.6 million.

This includes $19.5 million in collaboration revenue in the North American profit share territory $2 million in royalty revenue on take Casey sales in the European territory and $1.1 million, a net product revenue in other regions.

In the United States and significant order was placed on the last day of the quarter, which will not be recognizes revenue until the fourth quarter due to shipping terms.

Depending on ordering patterns, there are expected to be fluctuations in our quarter to quarter revenue recognition from time to time.

In Latin America full reimbursement takes place on a country by country basis, and can take some time, which can be further complicated by economic and political instability.

My savvy product revenue for the third quarter 2019, with $2.4 million due to the rarity of MPS seven we expect revenue for this product to be somewhat irregular from quarter to quarter and to build very gradually of ammo mentioned this typical for enzyme replacement therapies.

Shalini Sharpe: Depending on ordering patterns, there are expected to be fluctuations in our quarterly revenue recognition from time to time. In Latin America, full reimbursement takes place on a country-by-country basis and can take some time, which can be further complicated by economic and political instability. Metsevi product revenue for the third quarter of 2019 was $2.4 million.

You X O seven named patient revenue in the third quarter was zero point $7 million. We also recognized zero point $1 million in revenue this quarter from our research agreement with bear.

As we have put stated previously we continue to expect revenue from this fair agreement to be minimal going forward.

Shalini Sharpe: Due to the rarity of MPS-7, we expect revenues for this product to be somewhat irregular from quarter to quarter and to build very gradually, as Emil mentioned, as typical for enzyme replacement therapies. UXO07 named patient revenue in the third quarter was $0.7 million. We also recognized $0.1 million in revenue this quarter from our research agreement with Bayer. As we have stated previously, we continue to expect revenues from this Bayer agreement to be minimal going forward. Our total operating expenses were $143.8 million for the third quarter of 2019.

Our total operating expenses were $143.8 million fifth third quarter of 29 team.

For the past several quarters up to 20% of our operating expenses, excluding business development transactions like genetics and Arcturus have consisted of noncash items.

Our research and development costs were $100.1 million, which includes a 20 million dollar expense from the genetics upfront payment.

We expect our R&D costs to continue increasing over time as we continue advancing product candidates from early preclinical development into early and pivotal clinical studies.

[noise] crest DNA costs in Q3 were 41 million dollar.

We expect as DNA to increase overtime as we support our commercial program simultaneously launching across multiple geographies overtime. However, we expect our revenues to grow significantly into offset more and more of our operating expenses.

Net loss for the third quarter of 2019 with $113 million or 1.1 dollar 96 cents per share basic and diluted compared with a net loss of $87.3 million or $1.74 cents per share basic and diluted for the third quarter of 2018.

Shalini Sharpe: For the past several quarters, up to 20% of our operating expenses, excluding business development transactions like Genetics and Arcturus, have consisted of non-cash items. Our research and development costs were $100.1 million, which includes a $20 million expense from the Genetics Upfront Payment. We expect our R&D costs to continue increasing over time as we continue advancing product candidates from early preclinical development into early and pivotal clinical studies. Our SG&A costs in Q3 were $41 million.

The loss for the third quarter 2019 include the 20 million dollar R&D expense for the genetics upfront payments and a 2.2 million dollar unrealized gain from the fair value adjustment on the investment in our tourists equity.

For the first nine months of 2019 cash used in operations was $273.3 million. This includes $20 million for the genetics upfront payment in the third quarter of 29 team.

Shalini Sharpe: We expect SG&A to increase over time as we support our commercial program simultaneously launched across multiple geographies. However, over time, we expect our revenues to grow significantly and to offset more and more of our operating expenses. The net loss for the third quarter of 2019 was $113 million, or $1.96 per share basic and diluted, compared with a net loss of $87.3 million, or $1.74 per share basic and diluted, for the third quarter of 2018.

15.6 million dollar for the amended Arcturus license rights in the second quarter 2019, as well as adjustments for significant non cash charges, including stock based compensation expense at $62.3 million.

We ended the third quarter of putting 19 with $527.1 million in cash cash equivalents and available for sale investments, which is a net of the $20 million paid for the genetics collaboration this past quarter as well as $30 million paid to Arcturus for the amendment to that agreement in Q2 of 29 team.

Shalini Sharpe: The loss for the third quarter of 2019 includes a $20 million R&D expense for the Genetics Upfront Payment and a $2.2 million unrealized gain from the Fair Value Adjustment on the investment in Arcturus Equity. For the first nine months of 2019, cash used in operations was $273.3 million. This includes $20 million for the genetics upfront payment in the third quarter of 2019, $15.6 million for the amended Arcturus license rights in the second quarter of 2019, as well as adjustments for significant non-cash charges, including stock-based compensation expense of $62.3 million. We ended the third quarter of 2019 with $527.1 million in cash-to-cash equivalents and available-for-sale investments, which is a net of the $20 million paid for the We believe our cash resources should be sufficient to continue to support the initial years of launch for CRISPIDA and MEPCETI and allow us to continue to build and advance our clinical and translational research program pipeline. I would now like to turn the call back over to Emil. Thank you, Shalini.

We believe our cash resources should be sufficient to continue to support the initial years of launch for Christy the amex savvy and allow us to continue to build and advance our clinic clinical and translational research program pipeline.

I would now like to turn the call back over to anymore.

Thank you show me I'll now provide update on our clinical and preclinical programs and we'll turn the upcoming catalysts.

I'll start with you at all seven for our long chain fatty acid oxidation disorders.

Group of diseases with high mortality rate, even despite newborn screening and current treatment with MCT oil.

Last month, the FDA accepted our new drug application for you. It's old seven will work with the agency is a valid the filing over the next several months. The FDA has set a PDUFA date of July 32020 at this point they have indicated that they do not plan to hold Advisory Committee meeting to discuss the application.

Moving to detect real one or gene therapy program for Oren at the end transfer bandwidth deficiency or otcs deficiency, ODC deficiency that actually to recycle shorter that limits the body's ability to metabolize ammonia.

Inpatient ODP traditionally build up excess amounts ammonia their blood can quickly deteriorate into full metabolic prices suffering a neurologic deficit's other successively authorization coma and even depth.

We previously poor data for the first two course OTV study we've had two responding so normally for your chances for 72 to two weeks that maintain normalize ammonia is after discontinuing ammonia scavenger medications and liberalizing the diet.

They continue to do well off all therapy.

Emil D. Kakkis: I'll now provide an update on our clinical and preclinical programs, then we'll turn to the upcoming catalysts. I'll start with UX007 for long-chain fatty acid oxidation disorders, a group of diseases with high mortality rates even despite newborn screening and current treatment with MCT oil.

And our view these two patients demonstrated metabolic jury is achievable with DTF through a one.

We have since dose L. Three patients in the third quarter 2013 GE Cpqd.

Without seeing any safety concerns.

We will provide data from this cohort around the end of year.

We're also planning to steady addition, cohort at 2013 GC per kilo using prophylactic steroids as opposed to react discouraged based upon our own nonclinical data and data from others that prophylactic steroids could further enhance expression over and above that observed with increased dose alone.

Emil D. Kakkis: Last month, the FDA accepted our new drug application for UX007. We'll work with the agency as they evaluate the filing over the next several months. The FDA has set a production date of July 30, 2020. At this point, they have indicated that they do not plan to hold an advisory committee meeting to discuss the application.

We believe prophylactic steroid use could president has the consistency of expression for the you'd see program. We're encouraged by the potential treat this disease. We expect initial initiate this cohort with steroids in the first half of 2020.

Emil D. Kakkis: Moving to DTX-301, our gene therapy program for Ornithine Transcarbamylase Deficiency, or OTC deficiency. OTC deficiency is an X-linked recessive disorder that limits the body's ability to metabolize ammonia. Patients with ODC deficiency build up excessive amounts of ammonia in their blood and can quickly deteriorate into a full metabolic crisis, suffering from neurologic deficits and other toxicities leading to hospitalization, coma, and even death.

Switching to Dts floral one our gene therapy program collection storage fees type, one a or GST won a.

51 eighth costs by defective gene for the end, thank glucose sick facilities alpha, resulting in the inability to allow the liver tumor leaf glucose into the circulation. This leads to severe and sometimes life threatening hypoglycemia.

Today patients go to sleep thinking that the could die that night, if they don't wake up to their alarm and take their corn starch, while cornstarch can keep glucose levels up and improved survival does not directly address the disease and as long term complications.

Emil D. Kakkis: We've previously poured data for the first two cohorts of the OTC study. We had two responders who maintained normalized reogenesis for 78-52 weeks and have maintained normalized ammonias after discontinuing ammonia scavenger medications and liberalizing their diets. They continue to do well on all therapies. In our view, these two patients demonstrated a metabolic cure that is achievable with DTX-301. We have since dosed all three patients in the third cohort of 1E13-GC per kilo without seeing any safety concerns. We will provide data from this cohort around the end of the year. We're also planning to study an additional cohort at 1E13Gc per kilo using prophylactic steroids as opposed to reactive steroids based upon our own non-clinical data and data from others that prophylactic steroids could further enhance expression over and above that observed with increased doses alone.

Cornstarch therapy has stabilized and improve health.

Not a normal life by any measure.

We are encouraged that all six patients over to courts have shown meaningful clinical response to therapy at the two etwelve NCC 12, Tc rygiel dose levels.

This concludes improvements glucose control shown by time to hyperglycemia and reduction of course direct requirements. All three of the patient. The first dose cohorts are now off court start on breakthrough discord steroid therapy.

Second dose cohort of patients are showing a more meaningful production glass in storage as measured by the liver fat fraction and improved metabolism measured by lactate level.

These data indicates a core two doses showing greater transient expression and continue structural reductions and the stronger effect in the pathophysiology of the disease.

It was all we have moved to enrolling confirmatory expansion cohort of three patients at 612 GC per kilo dose.

And we expect to have data from this cohort in the first half of 2020.

Emil D. Kakkis: We believe prophylactic steroid use could further enhance the consistency of expression for the OTC program, and we're encouraged by the potential to treat this disease. We expect to initiate this cohort with steroids in the first half of 2020. Switching to DTX-401, our gene therapy program for glycogen storage disease type 1a, or GSD-1a. GSD-1a is caused by a defective gene for the enzyme glucose 6-phosphatase alpha, resulting in the inability of the liver to release glucose into the circulation. This leads to severe and sometimes life-threatening hypoglycemia.

Once we establish the dosing regimen, we initiate a phase three study as a predetermined dose.

I will also touch on our new agreement with gene genetics, biotherapeutics to advance and antisense oligonucleotides for the treatment of increments syndrome, a truly devastating disease instrument is a larger rare disease indication with approximately 22000 patients the United States and there are no approved treatment options today.

The disease mechanisms as well understood and DSO is a well validated class that is good approach for Angel syndrome, the targets the disease mechanism directly.

We recently made an upfront payment of 20 million, which includes an exclusive option to acquire genetics. We can exercise this option at any time prior to 30 days after the I'd for Gtx, one or two goes into effect.

Emil D. Kakkis: Today, patients go to sleep thinking that they could die that night if they don't wake up to their alarm and take their corn starch. While the corn starch can keep glucose levels up and improve survival, it does not directly address the disease and its long-term complications. So while cornstarch therapy has saved lives and improved health, it is not a normal life by any measure. We are encouraged that all six patients of the first two cohorts have shown meaningful clinical responses to therapy at the 2E12 and 6E12gc per kilodose levels. This includes improvements in glucose control shown by time to hypoglycemia and reduction in core and starch requirements.

You can also extend the option exercise and then later time point.

Gtx, one or two has received orphan drug designation and rare pediatric disease destinations designation.

Genetics is on track to file the idea and we will continue to update this program as advanced to the clinic.

Affinity minutes now discussing a number important milestones the coming months that we'll continue to drive our progress and we can move to the QNX.

For PC, though we expect.

Continued strong performance in North America, we believe the recent label expansion will further support. These efforts. We also continue to expand our reach with the Canadian launch and named patient sales and regulatory decision the Latin America.

We plan submitted a supplemental biologics license application DFT for could feed for the treatment T. O in first half of 2020, we're on track with the submission.

Well its population small over the next leach it isn't urgently ELD population with sometimes very severe disease that we believe will adopt the seat to over Fasi therapy based on our data to date.

Emil D. Kakkis: All three of the patients in the first dose cohorts are now off cornstarch or on greatly reduced cornstarch therapy. In the second dose cohort, all patients are showing a more meaningful reduction in glycogen storage as measured by the liver fat fraction and improvements in metabolism measured by lactate levels. These data indicate that CoR-2's dose is showing greater transgene expression and continued structural reductions and a stronger effect on the pathophysiology of the disease.

For us so seven.

Continue to work with the FDA review our end the eight working toward PDUFA date of July three for 2020.

We're encouraged by the construct discussion to date on the phase two data package. We just look forward to an opportunity to treat many more at the patients much more quickly. This early filings pending approval.

Emil D. Kakkis: As a result, we have moved to enrolling the confirmatory expansion cohort of three patients at 6E12Gc per kilo dose, and we expect to have data from this cohort in the first half of 2020. Once we establish the dosing regimen, we would initiate a phase 3 study at the predetermined dose. I will also touch on our new agreement with Gene Genetics Biotherapeutics to advance an antisense oligonucleotide for the treatment of Angelman syndrome, a truly devastating disease. Angelman is a larger rare disease indication with approximately 22,000 patients in the United States, and there are no approved treatment options today.

Moving to the gene therapy programs are two programs in GFT, one a and hope to see continued to progress will provide an update in OTI fee program around ended the year and we'll have data from the confirmatory GST one a cohort in the first half from 2020, which have already begun dosing.

Finally for the preclinical pipeline, we continue to advance for preclinical programs, including our gene therapy pro for with disease in the collaborative Gtx is so program Braintree and syndrome.

To summarize briefly execution by our commercial team third quarter continue to drive success of this could speed launch with two additional programs nearing potential commercialization with you.

Emil D. Kakkis: The disease mechanism is well understood, and ASO is a well-validated class. It is a good approach for Angel Syndrome, as it targets the disease mechanism directly. We recently made an upfront payment of $20 million, which includes an exclusive option to acquire Genetics. We can exercise this option at any time prior to 30 days after the IND for GTX-102 goes into effect, or we can also extend the option exercise at a later point.

Oh, seven Andy under review and the preceded sub mental Billy planned for own first half along that 70 for him give seven sets us up potentially have three commercial therapies treating for diseases in 2020.

Our gene therapy probes are advancing to the clinic toward phase three studies and we have a broke robust preclinical pipeline as well.

Emil D. Kakkis: GTX 102 has received orphan drug designation and rare pediatric disease designation. Genetics is on track to file the ID, and we will continue to provide updates on this program as it advances to the clinic. I'll spend a few minutes now discussing a number of important milestones in the coming months that will continue to drive our progress, and then we can move to the Q&A. For Christina, we expect to see continued strong performance in North America.

We continue to deliver on our goal of bring their patient grid. These without good treatment options and we have another important kelsen gene therapy, new product lives and Commercializations. We finished the year ahead into early 2020.

Let's move to your questions. Operator, if you please provide instructions for queuing a portion of the call.

Absolutely ladies and gentlemen, if you have a question at this time. Please press the star ended the number one key I know you touched on California.

A question has been answered you wish came with the shelf. Nick you can use plastic chunky, maybe remind participants that you are allowed to ask one question and one follow up question.

Emil D. Kakkis: We believe the recent label expansion will further support these efforts. We will also continue to expand our reach with the Canadian launch and the inpatient sales and regulatory decisions in Latin America. We plan to submit a Supplemental Biologic License application to the FDA for Chris Feeder for the treatment of TAO in the first half of 2020.

Your first question comes from the line of gene are wearing from Barclays. Please proceed.

Thank you for taking my question.

My first question is regarding launching Flds machine PDUFA date is offset just wondering what is your thoughts on pricing.

Emil D. Kakkis: And we're on track with the submission. While this population is smaller than XLH, it is an urgently ill population with sometimes very severe disease that we believe will adopt to over-phosphate therapy based on our data to date for USO 7. We continue to work with FDA as they review our NDA, working toward a production date of July 31, 2020. We are encouraged by the constructive discussion to date on the Phase II data package.

The second question is regarding the GST Wang last time, when we discuss that 35 gram of corn starch fasting challenge passes seems to interfere with sensitive glucose metabolism. Just wondering if you can share with us the latest thoughts.

Emil D. Kakkis: We just look forward to an opportunity to treat many more FAOD patients much more quickly with this early filing pending approval. Moving to the gene therapy programs, our two programs in GSD1A and OTC continue to progress. We'll provide an update on the OTC program around the end of the year, and we'll have data from the confirmatory GSD1A cohort in the first half of 2020, which has already begun dosing. Finally, for the preclinical pipeline, we're continuing to advance four preclinical programs, including our gene therapy program for Willis disease and the collaborative gene Tx ASO program for Angevin syndrome. To summarize briefly, the execution by our commercial team in the third quarter continues to drive the success of this CrisVita launch.

Optimize the test design, so that will be able to capture to clinical benefit.

Yes, very good well, we'll start with the Fob price, we certainly haven't price the product yet.

But I would let Charlie maybe discuss what.

No above the pricing without there at this point in time.

Sure Yeah. So as April said, we Havent made a final decision on pricing for that product yet, but you you probably know that the sell side models tend to range on lower aside for this product estimating somewhere between 50 to $100000 per patient per year.

Most likely because this is a small molecule therapy and so because of that the threed has expected lower in terms of rare disease pricing and we don't think thats, an unreasonable assumption, but we don't have a final decision on pricing.

Very good and gene I'll answer the question on GST, one a so that the challenge we were seeing in the GTN program is that the patients had time to type of the theme improvement and we're having Korn ferry production, but the amount of time improvement in the test was not nested quarreling with their ability to reduce or corn starch, which didn't quite make sense.

Operator: We have two additional programs nearing potential commercialization, with UX-07 NDA under review and the CrisVita Supplemental VLA plan for TIO in the first half, along with MAP-7 for MPS-7, that sets us up to potentially have three commercial therapies treating four diseases in 2020. Our gene therapy programs are advancing through the clinic toward phase 3 studies, and we have a robust preclinical pipeline as well. We continue to deliver on our goal of bringing therapies to patients with rare diseases without good treatment options, and we have a number of important milestones in gene therapy, new product values, and commercialization as we finish up the year ahead into early 2020. Let's move to your questions, operator. Can you please provide the instructions for the Q&A portion of the call? Absolutely. Ladies and gentlemen, if you have a question at this time, please press the star and then the number one key on your touchtone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key.

And when we began realized was happening is at the with Tesla being done three five gram starter given it was causing a glucose surge in these especially the co or two patients which drove down there glucose through an insulin respond.

While some of those patients were able to go with very low contracts during the week, but during the tests were actually driven down so what we've modified amended the protocol ready to reduce that to 10 grams or less of starts to we should see not see that kind of Hyperinsulinemic response, we think that will help demonstrate the difference between what the patients are.

Thing on their own without cornstarch compared to what they could do now when they have an enzyme in the limits releasing Lucas. So we think that small fix should help improve what we're seeing.

And we looked at that data in totality in that core to we felt good about the fact that we're having a very meaningful effect on GST, one and we proceeded ahead with that dose and cohort, we'll see that data soon.

Thank you.

Thank you Kim next question comes from the line is Chris Bateman from Piper Jaffray. Please proceed.

Gena Wang: May we remind our participants that they are allowed to ask one question and one follow-up question. Your first question comes from the line of Gena Wang from Barclays. Please proceed, seems like PDUFA data is all set. Just wondering, Amir, what are your thoughts on pricing? And a second question is regarding GSD-1A.

Thanks.

First.

At commercial question, Chris Vienna, So I think I heard just Shalini mentioned that.

There was a large order on the last day in a quarter, which I think.

Emil D. Kakkis: I think a lot of time when we discussed that, you know, 35 grams of corn starch fasting challenging tests seems to interfere with sensitive glucose metabolism. Just wondering if you can share with us the latest thoughts on optimizing the test design so that it will be able to capture true clinical benefit. Yes, very good.

Maybe played to as a driver of some quarter on quarter.

Choppiness, if you will but just doing some math on the patient numbers.

The 11 30 patients on reimbursed therapy Thats, if we just do the math from the prior two quarters that does represent a decent slowdown.

Shalini Sharpe: Well, we'll start with the FED price. We certainly haven't priced the product yet. But I would let Shalini maybe discuss what we know about the pricing, at least what's out there at this point in time. Sure, yeah, so as Emil said, we haven't made a final decision on pricing for that product yet, but you'll, you probably know that the cell side models tend to range on the lower side for this product, estimating somewhere between $50,000 to $100,000 per patient per year, most likely because this is a small molecule therapy, and so because of that, the street has expected lower in terms of rare disease pricing, and we don't think that's an unreasonable assumption, but we don't have a final decision on pricing. Very good.

In in patients I think it's 18% quarter on quarter, whereas the last two quarters were.

30, some percent. So just can you talk a little bit about that dynamic are we seeing a slow down or is that also something that's subject to some choppiness.

And I have a follow up thanks.

Well I think the 100 the 170 new start forms we think is.

Fairly consistent with what the plan has been seeing there may be some degree of flowing but I think this is sort of expected launch continues but we don't think has been ending side and I think theres, a little bit of timing issues, but.

At this point, we feel good about how is progressing and are not concerned about like a significant change, but we see the what you're seeing there, but I think view you saw all the numbers like a linear graph you would look at it as kind of being a steady progression.

Emil D. Kakkis: And Gena, I'll answer the question on GST-1A. So the challenge we were seeing in the GST-1 program was that the patients had a time-to-hypoglycemia improvement and were experiencing corn starch reduction, but the amount of time improvement in the test was not necessarily correlated with their ability to reduce their corn starch, which didn't quite make sense. And what we began realizing was that the way this test was being done, 35 grams of starch were given, it was causing a glucose surge in these, especially cohort 2 patients, which drove down their glucose through an insulin response.

Okay, and then a related question Im sorry, if you already addressed this anymore, but adding expanding a label to include.

It's as young as six.

What does it due to the prevalent patient pool, how much does that increase that.

So the label increases to allow instead of one year in up to allow six month and up six six but I'd say, but yes, it's really it's not a large change in the population.

Christopher Joseph Raymond: While some of those patients were able to go with very low constriction during the week, they were actually driven down during the test. So we've modified and amended the protocol already to reduce that to 10 grams or less. [inaudible] We proceeded ahead with that dose and cohort. We'll see that data soon. Thank you. Your next question comes from the line of Chris Raymond from Byber Jaffray. Please proceed. Thanks. First, a commercial question on Kris Vita.

But to our kids that are let's say eight 910 months that want to get on treatment as parents want them on treatment. So we do think it would be great for those patients with straight on Chris feed a rather than starting on phosphate.

Potentially get injured from that drug and then get could feed us so.

For six months or you don't the Foxley isn't really low enough. We don't think theres a need to go for six so we think the six month edition will allow us to treat kids and an optimal way.

Emil D. Kakkis: So, you know, I think I heard you, Shalini, mentioned that there was a large order on the last day of the quarter, which I think you guys maybe pointed to as a driver of some quarter-on-quarter Choppiness, if you will, but just doing some math on the patient numbers, the 1130 patients on reimbursed therapy, that's, if we just do the math from the prior two quarters, that does represent a So just can you talk a little bit about that dynamic, are we seeing a slowdown, or is that, and I have a follow-up. Thanks. Well, I think the 170 new start forums we think is...

Thank you.

Thank you Kim next question comes from the line of you're Rolling over there from Cowen. Please proceed.

Great, Thanks, and maybe a couple of questions.

Maybe one April for you with respect to the very slight shift you're seeing now but.

Yes, it looks like the number of adults. So the percentage of adults is increasing is it any sense as to what's driving that or is that just a natural cadence as you're going to find more and more prevalent patients and that sort of the newly diagnosed and then secondly, you can help us understand and Angel men with genetics, what would be the endpoints.

Emil D. Kakkis: Fairly consistent with what the plan has been seeing, there may be some degree of slowing, but I think this is sort of expected as launch continues, but we don't think there's been anything said, and I think there's a little bit of timing issues, but at this point, we feel good about how it's progressing and are not concerned about, like, a significant change. But we see what you're seeing there, but I think Okay, and then a related question. I'm sorry if you already addressed this, Emil, but adding, expanding the label to include kids as young as six, what does that do to the prevalent patient pools? How much does that increase that? So the label increases to allow, instead of one year and up, to allow six months and up. Six months, yeah, that's right, six months.

But you're going to be looking for its going to be obviously safety study initially, but what about the efficacy parameters. Thank you.

Okay. So.

In terms of the shift remember that we expect that 9000 patients Thats, where dolphin presell therapy.

But the main to visit kids have come in the clinic frequently and therefore, the c. the doctor frequently therefore, the docs and offer could FIDA more frequent basis.

If you look at what we've done a little over a year launch with pediatrics, we've actually wary treating 25% of the U.S. pediatric population in the first year, So which I think is a pretty incredible degree of penetration of a marketplace.

To have 25% of all expected piece in the United States to be on therapy, because natural to expect now as we reach out and and send our PDL teams out looking for adults that been lost a follow up and down outlined clinics were going to start to find those people and bring them into the fold and milk finally come to their clinic can get offer treatment I think the improved late.

Emil D. Kakkis: Yeah, so it's really not a large change in the population. But there are kids that are, let's say, 8, 9, 10 months old that want to get on treatment. The parents want them to get on treatment.

Yaron Benjamin Werber: So we do think it would be great for those patients to go straight on CRISPR-Vita rather than start on phosphate. Thank you for your time. Thank you. Your next question comes from the line of Yaron Werber from Calen. Please proceed to the very slight shift that you're seeing now, but it looks like the number of adults or the percentage of adults is increasing. Does that make any sense as to what's driving that, or is that just a natural cadence as you're going to find more and more prevalent patients in that sort of newly diagnosed? And then secondly, if you can help us understand Angelman with genetics, what would be the endpoints that you're going to be looking for?

Mobile will actually help a lot because the muscle diseases, the common problem and oral phosphate doesn't really do anything for it and so being able to have a distinct feature that we achieve with.

Could speed I think will bring some patients into maybe thought they didnt need treatment, but weren't really fully appreciating how much. They had so we expect to see a continued shift toward adults as time I think it just means we're finding more of the adults and we're also penetrating lot of the kids have come to clinic, but we do think in the end with the majority or nearly all pediatric pace.

And we'll should get on therapy in that a significant fraction of the dolls, perhaps half or more that Mike.

Emil D. Kakkis: It's going to be obviously a safety study initially, but what about the efficacy parameters? Thank you. Okay, so. In terms of the shift, remember that we expect 9,000 patients, that's where our dolls and 3,000 are paid. But the main difference is that kids come to the clinic frequently, and therefore they see their doctor frequently, and therefore their doctor can offer a confita on a more frequent basis.

Should be treated so we think this is a natural progression.

Now on the second question, you asked with genetics and.

And the endpoint.

We are beginning the program than to be clear genetics is really running the program and we have our own core team that sort of mirrored and supporting them and to helping do things.

Emil D. Kakkis: If you look at what we've done in a little over a year of launch with Piatrics, we've actually... We're already treating... 25% of the U.S. pediatric population in the first year or so, which I think is a pretty incredible degree of penetration of a marketplace to have 25% of all expected Peds in the United States be on therapy. So it's natural to expect now, as we reach out and send our PDL teams out looking for adults that have been lost to follow-up and outlying clinics, we're going to start to find those people and bring them into the fold, and they'll finally come to their clinic and get offered treatment. I think the improved label will actually help a lot because muscle stiffness is a common problem and oral fossil doesn't really do anything for it.

We haven't made all the decisions on the clinical endpoint program at this point I don't think we would talk about them. There's certainly a number of endpoints such as over it has used in their program and we certainly will look at a lot of these I look at the phase two beginning program.

As a first look and exploratory study and then as time goes on will help hone in on what we think that part of the approval by endpoints, we'd want to put into a program, but I wouldn't want commit to them at this point in time.

Yes.

Thank you.

Next question comes from the line of Maury Raycroft from Jefferies. Please proceed.

Everyone. Congrats on the progress and thanks for taking my questions.

I guess.

I wanted to ask a guidance question, just receiving provide any more clarity on what you're looking for to give more comfort with launch dynamics to provide more guidance on our Christina.

Emil D. Kakkis: So being able to have a distinctive feature that we achieve with CRIS-V that I think will bring some patients in who maybe thought they didn't need treatment but weren't really fully appreciating how much they had. So we expect to see a continued shift toward adults over time. And I think it just means we're finding more of the adults, and we're also penetrating.

Well I think maybe I should let showing talk about guidance and plan.

Sure well Maury so far we have provided a lot of granularity in terms of other metrics to give you a good sense of how the market is evolving over time and as the quarters go buy we are learning more and more about the trajectory of the product. So I think we'll get more comfortable giving guidance.

Emil D. Kakkis: A lot of kids have come to clinic, but we do think in the end, the majority or nearly all pediatric patients should get on therapy should be treated. So we think this is a natural progression. Now, on the second question you asked about genetics and endpoints, well, we're beginning the program, and to be clear, genetics is really running the program, and we have our own core team that's sort of mirroring and supporting them and helping do things. We haven't made all the decisions on the clinical endpoint program at this point. I don't think we will talk about them.

That is it's our aim to provide you guidance at some point, we just haven't committed to exactly when that is I think we'd like to make sure. We're very clear about the trajectory of the launch and.

What different quarters look like and what the dynamics look like and then we'll feel more comfortable giving you a better number.

Got it that's helpful and just as a follow up.

For for a one just wondering if you can recap what the gene regulatory regions are in the gene therapy contract and if you're planning on exploring goes and the expansion cohort or potentially in the phase three exploring those potentially leveraging those in some way.

Emil D. Kakkis: There are certainly a number of endpoints, such as OVID has used in their program, and we certainly will look at a lot of these. As a first look, an exploratory study, and then as time goes on, we'll help hone in on what we think are the approval land points we'd want to put into a program, but I wouldn't want to commit to them at this point in time. Thank you. Your next question comes from the line of Maury Raycroft from Jefferies. Please proceed. Hi everyone, congrats on the progress and thanks for taking my questions. I guess I wanted to ask a guidance question just to see if you can provide any more clarity on what you're looking for to get more comfortable with Launch Dynamics to provide more guidance on CRIS VITA.

What we know.

Or is that the promoter we're using as a three Columbus region of the GE is key to compete is.

Promoter includes element that that respond to steroids.

He elements that increase expression substantially it also has elements that for insulin might depress it gone by and do fit.

And in fact, it really is designed to coordinate and integrate your body's needs with regard to glucose, which we think is a unique feature of our for on program and we can see that happening that of the steroids at week six induced Hyperglycemic response, which is what will happen the normal people, but most.

Maury Raycroft: Well, I think maybe I should let Shalini talk about guidance and plans. Sure. Well, Maury, so far, we have provided a lot of granularity in terms of other metrics to give you a good sense of how the market is evolving over time. And, you know, as the quarters go by, we are learning more and more about the trajectory of the product. So I think we'll get more comfortable with giving guidance. That is, it's our aim to provide you with guidance. At some point, we just haven't committed to exactly when that is. I think we'd like to make sure we're very clear about the trajectory of the launch and what different quarters look like and what the dynamics look like, and then we'll feel more comfortable giving you a better number. I got it.

GFT one a patients do not respond to started normally because they can't release Lucas they actually get they go the other way they get hypoglycemic.

We studied the regulation in vitro as well and liver cell lines and learn we know a lot about it and we think that is going to be important.

One thing it does give us the opportunity to use steroids to induce the gene expression, if we wanted to.

It's something that certainly is a tool we have in our tool box that we wanted to do that at some point in time, but at this point, we want to let patient.

Stabilize get off their core search completely let their body come into.

A normal regulation or they're not all in some he Mick and high starch, all the time and they can get into a normal cycle of being.

Between.

And glucose and I think that will allow the gene expression to build even further we would expect in that might help them. So once they get up to start to get stabilized, we'll see how they're doing but we do have the opportunity you steroids for example to induce expression if we wanted to.

Shalini Sharpe: That's helpful. And just as a follow-up, for 401, just wondering if you can recap what the gene regulatory regions are in the gene therapy construct, and if you're planning on exploring those in the expansion cohort or potentially in phase three, exploring those and potentially leveraging those in some way. What we know, Maury, is that the promoter we're using is a 3 kilobase region of the G6Pase promoter. It includes elements that respond to steroids, GRE elements that increase expression substantially. It also has elements that, for insulin, might suppress it, while glucon might induce it.

Got it understood. Thanks for taking my questions.

Thank you. Your next question comes from your line is Cory Kasimov from JP Morgan. Please proceed.

Hi, guys. Thanks for taking my question was does not see on for Corey.

So for the four one study on to follow up on Junos question, how should we be thinking about the comparable quality between data sets from the current versus amended cornstarch challenge in the context of thinking about the go forward test for this program.

Emil D. Kakkis: And in fact, it really is designed to coordinate and integrate your body's needs with regard to glucose, which we think is a unique feature of our 4.0.1 program. And we can see that happening. The steroids at week 6 induced a hyperglycemic response, which is what happens in normal people. GSD1A patients do not respond to steroids normally because they can't release glucose. They actually get, they go the other way; they get hypog

Well, we will so in terms of testing.

The the confirmed to covert we initiated we'll have a new start testing regimen from baseline so you'll have baseline for them.

But I would say too for the other ones will test some from what they were honored with a corn starch and then we'll have a repeat that will not have the current starts you look head to head what I would say views rather than comparing the for the first two court rather comparing baseline to end game, what I would say to you it doesn't matter what their baseline. His question is can they stay.

Emil D. Kakkis: We studied the regulation in vitro as well as in liver cell lines, and we learned a lot about it, and we think that it's going to be important. One thing it does give us the opportunity to use steroids to induce gene expression if we want to. It's something that certainly is a tool we'd have in our toolbox if we wanted to do that at some point in time, but at this point, we want to let patients get stabilized, get off their core stretch completely, let their body come into, www.youtube.com.uk. Got it, understood. Thanks for taking my question. Thank you. Your next question comes from the line of Corey Kazimov from J.P. Morgan. Please proceed. Hey guys, thanks for taking my question. This is Matthew and for Corey.

Off.

It can they stay.

In normal sugar levels for the entire night, if they can do that.

With the new regimen, then that's the answer the answer is they can do that now and they couldn't do it before so you don't actually have to compared based on to get to answer the clinical meaningful if we keep all six patients from going hyperglycemic once or off starch and they're not getting the they're not getting the high starch and the test.

That's your answer it's working.

Got it thanks, Andrew has quickly on the 301 program.

Given the data around year end in the prophylactic steroids.

Cohort as expected.

How should we just thinking about timelines to phase three study.

Well because we are we're playing to the steroids arm for that that would bring it out a little further for LTC, because assuming GFT one goes straight through than that would be faster and LTC would have a little bit more.

Matthew: So for the 401 study and to follow up on Gina's question, how should we be thinking about the comparability between data sets from the current versus amended corn starch challenge in the context of thinking about the go forward dose for this program? Well, in terms of testing, the confirmatory cohort we initiated will have a new starting testing regimen from baseline, so you'll have baselines for them. But I would say to you, for the other ones, we'll test them from what they were with the cornstarch, and then we'll have a repeat that will not have the cornstarch. You'll see them head-to-head. What I would say to you is, rather than comparing baseline to endgame, what I would say to you is, it doesn't matter what their baseline is. The question is, can they stay off? Can they stay at normal sugar levels for the entire night?

To do before going.

The phase three but.

We would expect though at least.

The first half year to have a sense for what the fee to plan is I mean with a piece. We plan is for LTC and timeline going forward I think if we can show that were actually during the majority of patients metabolic carrying the majority of patients.

With a steroid regimen I think least you'll have an answer that there is a product there and it can move forward, but it would be a little after the the GST one program, which is.

Actually moving faster at this point in time.

Great. Thanks for taking my question.

Okay.

Thank you. Your next question comes from the line of Laura Chico from Wedbush. Please proceed.

Emil D. Kakkis: If they can do that with the new regimen, then that's the answer. The answer is that they can do that now, and they couldn't do it before. So you don't necessarily have to compare to baseline to get the answer to this clinically meaningful question. If we keep all six patients from going hyperglycemic once they're off starch, and they're not getting the high starch in the test. That's your answer. It's worked before. Scott, I got it.

Good afternoon, and thanks for taking my question I guess, one first on October seven I think youve spoken of this opportunity representing about two to 3000 your expectations I'm curious if you will actually have perhaps.

A number on the number of identify patients.

Prior to launch just to get a better estimate of perhaps the addressable treatment market.

Emil D. Kakkis: Thanks. And then just quickly on the 301 program, given the data around year end and the prophylactic steroids, cohort expected afterward, how should we be thinking about timelines for phase three? Well, because we are planning to do the steroid arm for that, that would bring it out a little further for OTC, because assuming GSD-1 goes straight through, then that would be faster, and OTC would have a little bit more to do before going. Unknown Speaker Page 10 of 10, You know, in the first half of the year to have a sense of what the phase two plan is.

Then a separate question.

Dcxthree I want to take I, just missed it but when might we get the data from that prophylactic steroid cohort. So that's how does that factor into your plans for example.

Okay.

So for launching fatty acid defects in the United States on all 50 safely our newborn screening and we know there is around 100 150 range diagnosed every year. So the patient identification program will be different now the challenges patients, let's say over age 10 may have been myth and we will have to work.

Emil D. Kakkis: I mean, what the phase three plan is for OTC and the timeline going forward. And I think if we can show that we're actually curing the majority of patients with, metabolically curing the majority of patients with a steroid regimen, I think at least you'll have an answer that there is a product there and it can move forward. But it would be a little after the GSD-1 program, which is potentially moving faster at this point in time.

On finding those patients.

But we should have maybe for 10 years of patients should have been diagnosed.

Which I think will be an important van der launching especially since every year. When you get a new group of patients diagnosed to have the drug available that.

We'll be covered by insurance, rather than something you're paying out of pocket and would have information about it would suggest is superior at preventing major hospitalization.

Emil D. Kakkis: Great, thanks for taking my question. Thank you. Your next question comes from the line of Laura Chico from Wedbush. Please proceed. Good afternoon.

I think would be good drivers for adoption, we won't be able to tell you exactly the adopt the addressable population, but because of newborn screening we could probably predict for you approximately based on estimates of life span with private population should be.

Laura Kathryn Chico: Thanks for taking the question. I guess one first on UX007. I think you've spoken of this opportunity representing about 2,000 to 3,000 U.S.-based patients. I'm curious if you will actually have, perhaps, a number on the number of identified patients. Prior to launch, just to get a better estimate of perhaps the addressable treatment market. And then, a separate question on DTX-301. I think I just missed it, but when might we get the data from that prophylactic steroid cohort, and then how does that factor into your plans for advancement? Thank you. So for long chain fatty acid defects, in the United States, now in all 50 states, they are a newborn screen, and we know there are around 100, 150 in the range diagnosed every year.

But we have been developing our techniques around.

Patient diagnosis and the team that's been doing it and so we feel very good about our ability to find these patients.

Most of them, we'll be in medical clinics and about 160 centers. So it's a little bit more focus to group that might be with let's say adult exelate, which is more like a few thousand.

So we think we could do it with a relatively focus team.

And because we've been supporting compassion use early access and.

Have a number of patients on long term therapy at a number of centered around the U.S.. There's a high awareness for the product already and so we feel that will well given an opportunity to.

Emil D. Kakkis: So the patient identification program will be different. Now the challenge is patients, let's say over age 10, may have been missed, and we will have to work on finding those patients. But we should have maybe the first 10 years of patients diagnosed, which I think will be an important band you're launching, especially since every year when you get a new group of patients diagnosed, the drug will be available, and will be covered by insurance rather than something you're paying out of pocket and would have information about it that would suggest it's superior at preventing major hospitalizations, which I think would be good drivers for adoption.

To move more quickly as we move ahead.

So the Lessing EPS was 301 prophylactic steroids.

So we will be says we're going to get the the E 13 dose.

Data.

Around the ended the year.

For.

No without with reactive steroids and.

And then we'll be initiating the prophylactic steroids amendments already been filed a few months ago. So it's already out there in play so we should be able to proceed and we're working with our patient diagnosis of us in light of ODC patients.

So that we would start enrolling that patients the first part of the year.

I had expected days to take some time to get through to get an updated it really be confident that were changing course or improving efficiency and we'll be able to compare with or without prophylactic series and the tell us whether thats, helping or not I'd expect around midyear, we would have a fuel for it but we havent set a precise timeline at when we'll know exactly.

Emil D. Kakkis: We won't be able to tell you exactly the addressable population, but because of newborn screening, we could probably predict for you, approximately, based on estimates of the lifespan, what the prevalent population should be. But we have been developing our techniques around patient diagnosis and a team that's been doing it. And so we feel very good about our ability to find these patients. Most of them will be in medical clinics that are about 160 centers. So it's a little bit more focused a group than might be with, let's say, adult XLH, which is more like a few thousand. So we think we could do it with a relatively focused team.

Results it depends on enrollment.

Thanks very much.

Thank you. Your next question comes from the line its Salveen rich stem from Goldman Sachs. Please proceed.

Thanks for taking your questions. This is Andrew on for Celgene on my first one just a follow up to the upcoming Xtremio. One cohort three I'm can you help frame for us what the expectations are there and how positive response in Q3 patients is still the bar to advance the program.

Emil D. Kakkis: And because we've been supporting compassionate use, early access, and have a number of patients on long-term therapy at a number of centers around the U.S., there's a high awareness for the product already, and so we feel that will give an opportunity to move more quickly as we move ahead. So the last thing you have to do is 301 prophylactic steroids. So what we said is we're going to get the data around the end of the year for, No, without, and with reactive steroids. And then we'll be initiating the prophylactic steroids. Amendment It's already been filed a few months ago, so it's already out there in the world.

Or if that decision is more dependent on the outcome of this additional cohort that's using prophylactic steroids.

Well I think we are we've said that two at a three patients showing response would tell us that the dose is probably right. The steroids, we'd hope would increase that to be more consistent particularly.

If there to the difference between males and females, which we we believe may be true, but we're not 100% certain at this point. So the idea of the steroids with the Netlists. They increased the peak, but increase the consistency of response.

Emil D. Kakkis: So we should be able to proceed, and we're working with our patient diagnosis team, obviously the line of OTC patients, so that we would start enrolling that patient for the first part of the year. I'd expect the data to take some time to get through, to get enough data to really be confident that we're changing the course or improving efficiency, and we'll be able to compare with and without prophylactic steroids to tell us whether that's helping or not. I'd expect around mid-year we would have a feel for it, but we haven't set a precise timeline yet when we'll know the exact results. It depends on enrollment. Thanks very much.

Our expectation, we'd probably do the steroid arm anyways, we will have made the product available to do it.

But.

Our goal was to get at least two at a three to say that we're progressing the program.

That our responder so weve.

We think thats a reasonable targeted to at least tell us that the drug is effective enough and then if we can get this at effect of steroids that would help tell us with those combination would give us.

Salveen Jaswal Richter: Thank you. Your next question comes from the line of Salveen Richter from Goldman Sachs. Please proceed. Great. Thanks for taking our questions. This is Andrea on behalf of Salveen.

Confidence that we don't need to go higher than we have a high enough dose.

And I'd remind you that we had.

Complete responders that bought shares at 212, and 60 12, so either team has kind of.

Emil D. Kakkis: My first question is, just as a follow-up to the upcoming DTX 301 Cohort 3, can you help frame for us what the expectations are there and if a positive response in two of the three patients is still the bar to advance the program, or is that decision more dependent on the outcome of this additional cohort that uses prophylactic steroids? Well, I think we are. We've said that two out of three patients showing a response would tell us that the dose is probably right, and the steroids we'd hope would increase that to be more consistent, particularly if there's a difference between males and females, which we believe may be true, but we're not 100% certain at this point. So the idea of steroids would not necessarily increase the peak but increase the consistency of response.

Substantially more and so the hope is a series would allow those patients that seem more resistant to respond to it in a similar way to the response, we've already had so.

Summarize we're looking for two out of three responders, but we would likely to the steroid cohort, regardless because we already have the drug in hand.

Got it makes sense and then just secondly on.

As the launch has continued and you've you've kind of monitor it does.

Do you have updated metrics and how many physicians are repeat prescribers and what if any or any of the gating factors.

The type of repeat behavior.

Well.

A lot we have actually it was.

Emil D. Kakkis: Our expectation is that we would probably do the steroid arm anyways; we'll have made the product available to do it. [inaudible] Our goal was to get at least two out of three to say that we're progressing the program, and that are responders. We think that's a reasonable target to at least tell us that the drug is effective enough. And then, if we can get an effective steroid, that would help tell us what those combinations would give us. Confidence that we don't need to go higher, that we have a high enough dose. And I'd remind you that we have.

670 unique prescribed but first let's let's be amazed that that number to start with.

Because it is an amazing number I've been in the rare disease visit forever never at 670 individual scribes for anything globally, even so it's a lot.

That is partly the reach that we've achieved that PDL team in finding all these docs and feeding them to the reps and that process really allowed us to do that.

About.

Two thirds of the of the docs have done.

Basically one script and about one third have done more than one script and what we see that fraction that have done more than one script is holding steady so as we add new prescribers. Some of the one per square groups, becoming a to prescribe or more group and we see that progression. So that two thirds, one third ratio, it's been pretty consistent for last.

Emil D. Kakkis: Complete Responders, Metabolic Cures at 2E12 and 6E12. So E13 is kind of, you know, substantially more. And so the hope is the steroids will allow those patients that seem more resistant to respond to it in a similar way to the response we've already had. To summarize, we're looking for 2 out of 3 responders, but we would likely do the steroid cohort regardless because we already have the drug in hand. Got it, makes sense. And then just secondly, on CRISPR Vita, as the launch has continued, and you've, you've kind of monitored this, do you have updated metrics on how many physicians are repeat prescribers? And what, if any, are any of the gating factors for this type of repetitive behavior?

So what we see as people try it out with a patient they get the feedback and most of the feedback is quite profound and then people start adding prescription. So I think that base will both the base a prescribed will help bode well for continued growth of the product.

But.

It does take one test a response to the people start adding secondary patients I think the other thing as many doctors are testing out the reimbursement situation because they don't want to get caught in a quagmire if theres any trouble are.

Emil D. Kakkis: Well, a lot we have actually, it was, 670 unique prescribers. First, let's be amazed at that number to start with. Because it is an amazing number. I've been in the rare disease business forever, and I've never had 670 individual subscribers for anything globally. So it's a lot.

Ultra care team is extremely good and I certainly when I talk with Piazza number them know their ultimate care team member by name.

Which means they have building relationships. The idea is it would take that hassle factors that we can.

Emil D. Kakkis: That is partly the reach that we've achieved with the PDL team and finding all these docs and feeding them to the reps, and that process really allowed us to do that. About two-thirds of the docs have done basically one script, and about one-third have done more than one script. And what we see is that fraction that has done more than one script is holding steady. So as we add new prescribers, some of the one-prescriber groups are becoming two-prescriber or more groups, and we see that progression. So that two-thirds, one-third ratio has been pretty consistent for the last few quarters.

In terms of dealing would have to be dealt with in order to get things done for patients but.

We think that Thats been really important part going as we commit patient get treated one way or another we put them on fast start and will if there's any hang up we also commit to get them them free drug. So the doctors feel like we're never going to pull regard under their patiently be confident we're going to stand behind them.

If they offer this to patients that they're going to get treated.

How we make it work and I think we need to keep doing that people get comfortable that's not just words amina.

Emil D. Kakkis: So what we see is people try it out with a patient, they get feedback, and most of the time the feedback is quite profound, and then people start adding prescriptions. So I think that the base of prescribers will help bode well for continued growth of the product, but it does take one test. Transcripts provided by Transcription Outsourcing, LLC. The UltraCare team is extremely good, and I certainly, when I talk with PIs, a number of them know their UltraCare team member by name, which means they are building relationships, and the idea is that we take that hassle factor as best we can.

Great. Thanks, so much color.

Thank you Sir your next question comes from Brian It's Adam Walsh from Stifel. Please proceed.

Okay guys. Thanks for taking my questions a couple of quick ones here. The first one is as we look across.

Latin America for Chris fee that you had mentioned that for both Argentina, and Colombia, you've seen named patient sales go up and in Brazil in the process of reimbursement through the Ministry of health, There and I'm, just curious where or when would we expect some kind of inflection point out of Latin America in your.

Emil D. Kakkis: You know, in terms of dealing with what would have to be dealt with in order to get things done for patients, but we think that that's a really important part. The other thing is we commit to patients getting treated one way or another. We put them on Fast Start. And we'll, if there's any hang up, we also commit to getting them free drugs. So the doctors feel like we're never gonna pull the rug out from under their patients. And they'd be confident that we're gonna stand behind them.

Major countries there when it comes to approvals reimbursement and patient access and then I have one follow up thanks sure. So obviously in Latin America, Brazil is the largest factor and the government. There. The current regime has been changing things and.

Trading uncertainties for how they're going to proceed we have a fairly large Q of patients going through the litigation process and we as I said, we've had first couple approved.

Emil D. Kakkis: And if they offer this to patients, they're going to get treated. And that's how we make it work, and I think we need to keep doing that. People get comfortable that it's not just words that mean it.

We'd expect that process to start get going but it has taken longer than we would have normally expected.

So I would say the Brazil process of getting reimbursement through litigation processes, what's going to essentially start driving the Brazilian launched the actual formal process.

Emil D. Kakkis: Great, thanks so much for the color. Thank you. Your next question comes from the line of Adam Walsh from CIFL. Please proceed. Okay, guys, thanks for taking my questions. A couple of quick ones here.

Can take some time in for most companies they're the most of revenue are getting from Brazil is coming from.

Maurice Thomas Raycroft: The first one is, as we look across Latin America, for Chris Vita, you mentioned that in Argentina and Colombia, you've seen named patient sales go up, and in Brazil, you're in the process of reimbursement through the Ministry of Health there. And I'm just curious, where or when would we expect some kind of inflection point in Latin America in your major countries there when it comes to approval? Reimbursement and patient access, and then I have one follow-up. Sure, so obviously in Latin America, Brazil is the largest factor, and the government there, the current regime has been changing things and creating uncertainties for how they're going to proceed.

The basically the litigation process for Argentina, we are actually going to files, well Argentina because.

To get the named patient program to accelerate further there is a belief that we need to file and so weve.

Agreed to do that and file there and actually try to drive the formal reimbursement.

I think it's going to take a little bit of time to get going but we are getting revenue and we will have a great team down there and just.

Things in Latin America can be complicated both politically and economically but we feel comfortable there's a strong drive for the product and people are aligning up and queuing up in the litigation process. In those cases are coming through and we believe that will start generating revenue, but I don't know who will be Sakhalin inflection point I think we'd start seeing some steady.

Emil D. Kakkis: We have a fairly large queue of patients going through the litigation process, and as I said, we've had the first couple approved. We'd expect that process to start, get going, but it has taken longer than we would have normally expected. So I would say the Brazilian process of getting reimbursement through the litigation process is what's going to essentially start driving the Brazilian launch. The actual formal process, Tazeen Ahmad, Yigal Nochomovitz, Joseph Schwartz, Emil Kakkis, Yaron Werber, Gena Wang, Anupam, If we get the named patient program to accelerate further, there is a belief that we need to file. [inaudible] Things in Latin America can be complicated, both politically and economically, but we feel comfortable that there's a strong drive for the product, and people are But I don't know if it will be exactly an inflection point.

Growth in the revenue from Latin a mark over time, we realize Latin America, the huge part of the value for Chris feed for us. So we are not under under estimating or under investing with required to produce.

Reasonable product revenue from Chris treat the in Latin America.

Okay, Great. That's helpful and one quick follow up here on you X tableau seven.

Our long chain fatty acid oxidation disorder. The FDA indicated that there won't be in AD come to you, but also indicate it's clear that theres not a priority review I'm just curious.

You might have thought there'd be a priority review given the unmet need and kind of the dire circumstances of the condition and then on the other hand, you might have thought there would be an AG given kind of unconventional nature of the clinical trial program that underlies the Dan da So just any commentary there would be great. Thank you.

Emil D. Kakkis: I think we'll start seeing some steady growth in revenue from Latin America over time. You know, reasonable product revenue from Crisprita in Latin America. Hey, great, that's helpful. And one quick follow-up here on UX007 for long chain fatty acid oxidation disorder: the FDA indicated that there won't be an ADCOM for you, but also indicated it's clear that there's not been a priority review. I'm just curious, you know; you might have thought there would be a priority review given the unmet need and kind of dire circumstance of the condition. And then, on the other hand, you might have thought there would be an ADCOM given the kind of unconventional nature of the clinical trial program that underlies the NDA. So just any commentary there would be great.

Sure well we've had.

Good part of the year of discussion with FDA and I think we kind of understand perspective.

We requested to file a phase two data that was not randomize control data just remember and our goal is to short cut the timeline and the investment expense of doing phase three and potentially taking four five years and does the millions of dollars, which.

Our goal was to file earlier, because you don't have ran with 12 day that does change perspective, whether we've proven its better than MCT or not but we think that data do showed superior and I think theres a procedural question in their mind and we've got standard review for that reason, but they agree that this important there have been very constructive understanding it.

And so it's a little bit more of a technical issue from the Advisory Committee standpoint, I don't think they have any debate that the drug is there and useful and therefore there was there wasn't really a reason driving the advisory committee.

Joseph Patrick Schwartz: Sure, well, we've had a good part of a year of discussions with the FDA, and I think we kind of understand the perspective. We requested to file off the Phase 2 data that was not randomized control data, just to remember.

And so I look at this is sort of up.

Procedural step and how they approach a drug filed a phase two like this and.

Emil D. Kakkis: And our goal was to shortcut the timeline and the investment expense of doing phase 3 and potentially taking 4 or 5 years and dozens of millions of dollars. Our goal with the file earlier, because we don't have a randomized control study, that does change perspective on whether we've proven it's better than MCT or not, but we think the data do show it's superior, and I think there's a procedural question in their minds, and we've got standard review for that reason, but they agree that it's important, they've been very constructive in understanding it, And so it From the advisory committee standpoint, I don't think they have any debate about whether the drug is there and useful, and therefore, there wasn't really a reason for the advisory committee. And so I look at this as sort of a... Transcribed by https://otter.ai, in the presence of an existing product MCT like oil. We're encouraged by it, Frankly.

In the presence of an existing product MCT like oil.

We're encouraged by it frankly I think it tells US I think we can get through to approval.

We're not predicting it but I think the FDA has been I think very collaborative disk and discussing application. So we feel comfortable we can move forward and have great chance getting approved and being able to watch this for FMT patients.

Thank you.

Thank you. Your next question comes from the line as Joe said squad from ESB Leerink. Please proceed.

Thanks, very much actually.

Continue on the last thread there.

Given you.

And others other investigators have generated a lot of data for you X years or seven.

On different endpoints amongst different patients in different settings, what do you most want to see end up on the label and what are the most probable scenarios that could play out based on your interactions with the FDA today.

Joseph Patrick Schwartz: I think that tells us that I think we can get through to approval. We're not predicting it, but I think the FDA has been, I think, very collaborative in discussing the application with us, and we feel comfortable that we can move forward and have a great chance of getting approved and being able to launch this for FAOD patients. Thank you. Thank you. Your next question comes from the line of Joseph Schwartz from SVB Larynx.

Well one thing I'd point out to you just that different I think from let's say oncology drugs you may be looking at time.

In rare disease Dread the best labels says that you have so seven has indicated to treat long chain fatty acid oxidation defect patient period.

Emil D. Kakkis: Please proceed. Thanks very much. Actually, I will continue on the last thread there. Given you and others, other investigators have generated a lot of data for UX007, different endpoints amongst different patients and different settings, what do you most want to see end up on the label? And what are the most probable scenarios that could play out based on your interactions with the FDA to date? Well, one thing I'd point out to you, Joseph, that's different, I think, from, let's say, oncology drugs that you may be looking at at the time. In rare disease drugs, the best label says that USO7 is indicated to treat long-chain fatty acid oxidation defect patients, period. That's all you want on a label. You really don't want to do a lot of fine crafting.

That's all you want on label.

You really don't want a lot of fine crafting you want that there and the study is the study and the data we presented.

Other assets the label don't Miss they have so much impact as long as the disease indicated as though limitations in that indication statement. That's what we're most comfortable with.

And I would point out to you that whether superior or not is one of the question.

Without around my study, but I think there's been a number of rare disease drugs approved with even noninferiority levels that are actually done fine I think.

Physician community very aware of the product, we get dozens of requests for emergency use.

And we've been supplying us with lot of experience out there as well so our goal with the FDA is to find a reasonable place how to lay bliss and how to support that label with real world data.

Joseph Patrick Schwartz: You want that there, and the study is the study in the data we presented. Other aspects of the label don't necessarily have so much impact, as long as the disease is indicated and there are no limitations in that indication statement, then that's what we're most comfortable with. And I would point out to you that whether it's superior or not is one of the questions around my study, but I think there have been a number of rare disease drugs approved with even non-inferiority labels that are actually done fine.

Disease marketing program data to help support the value of U.S.. So seven a we're confident that.

Yeah, So seven does improve outcomes for patients the significant way.

But we Didnt, we filed our phase two we didnt have randomized control study and I think thats the one distinct difference.

Okay. That's very helpful. Thanks, and then in your discussions with payers.

What have they been most focused on an order.

Emil D. Kakkis: I think the physician community is very aware of the product. We get dozens of requests for emergency use, and we've been supplying it. So there's a lot of experience out there as well.

To be confident that you X series or seven presents a.

And advantage versus MCT oil.

Joseph Patrick Schwartz: So our goal with the FDA is to find a reasonable place to label it and how to support that label with real-world data. Transcripts provided by Transcription Outsourcing, LLC. Ux07 does improve outcomes for patients in a significant way, but we didn't, we filed off phase two, we didn't have a randomized control study, and I think that's the one distinct difference. Okay, that's very helpful.

Well, we've shown both payors and occurred.

The results of the study and most are.

Preston compelled because it is.

Normally with rare disease and I've been in a lot of program.

Generally really hard to get for example, a 77% reduction in the media number of days in the hospital for five and half days to want to half over an 18 month period.

And then to followed for another 18 months and have the median go to zero.

Emil D. Kakkis: Thanks. And then, in your discussions with payers, what have they been most focused on in order to be confident that UX007 presents an advantage versus MCT oil? Well, we've shown both payers and dockers.

Right goes even lower after three years.

These you don't see that kind of data that has that direct pharmacoeconomic impact on patients and.

The numbers are large and those of statistically significant so.

We've had very good response to that both from doctors and payers frankly, and we feel pretty comfortable that theres. A good case for why this drug should be used to help prevent costly and disastrous catastrophic hospitalizations.

Joseph Patrick Schwartz: The results of the study, and most are impressed and compelled because it is, Normally, with rare diseases, and I've been in a lot of programs. Generally, really hard to get, for example, a 77% reduction in the median number of days in the hospital from 5 12 days to 1 12 over an 18-month period, and then to follow it for another 18 months and have the median go to zero. Right, it goes even lower after three years.

Makes sense, thanks very much.

Thank you next question comes from the Ryan Anthony said Baker from JMP.

Please proceed.

Hi, This is John on for Lisa just two questions from me, Jim I notice of your Cline gene therapy manufacturing capacity and you're going to have enough clinical supply for.

Emil D. Kakkis: You don't see that kind of data that has that direct pharmaceutical impact on patients, and the numbers are large, and those are statistically significant. So we've had a very good response to that, both from doctors and payers, frankly, and we feel pretty comfortable that there's a good case for why this drug should be used to help prevent costly and disastrous catastrophic hospitalization. Makes sense. Thanks very much.

All the studies throughout next year, and then just on cost of sales I saw pretty substantial quarter over quarter increase is there anything behind that number is that something we should look for moving forward or is that kind of a one off thanks, well talk about gene therapy manufacturing in less than Sean and deal with the financial part.

Joseph Patrick Schwartz: Thank you. Your next question comes from the line of Liisa Bayko from JMP. Please proceed. Hi, this is John on behalf of... Questions from me.

So on the gene to manufacturing we are using contract manufacturers, we develop the process and our Woburn facility with our own proximate team vault fully fledged full.

John: Can you remind us of your current gene therapy manufacturing capacity and if you're going to have enough clinical supply for all the studies throughout NICU? And then just on cost of sales, I saw a pretty substantial quarter-over-quarter increase. Is there anything behind that number?

Cost of these were how to development produce.

We are building out our call it control lab to actually do analytical testing ourselves, which will have operational.

Next year, which will allow us to accelerate the testing and release of product made but we're continuing youth several contract manufacturers across the country.

Emil D. Kakkis: Transcribed by https://otter.ai, Well, I'll talk about gene therapy and manufacturing, and then I'll deal with the financial part. So for gene type manufacturing, we use contract manufacturers. We develop the process at our Woburn facility with our own process development team.

Now with time, we plan and we are planning signing.

Our own manufacturing plant as well, but it's called the program at this point will depend on contract manufacturers.

Potentially our own testing lab.

Shalini Sharpe: We develop fully fledged processes for how to develop and produce. We are building out our quality control lab to actually do analytical testing ourselves, which we'll have operational next year, which will allow us to accelerate the testing and release of product-made. But we're continuing to use several contract manufacturers across the country. Now, with time, we plan, and we are planning and designing. Our own manufacturing plant as well, but the scope of the program at this point will depend on contract manufacturers and potentially our own testing lab. Currently, we've actually been running a number of the runs in preparation for phase three, and we will have. We've increased the investment in that to allow us to move more promptly ahead with the Phase 3 program, and we'd expect to have accumulated enough product to start and run the Phase 3s well before those programs get The Contract Mayfax.

The currently we've actually been running a number the runs in preparation for phase three and we will have we've increased the investment in that to allow us to move more promptly ahead with the phase three program and we'd expect to have accumulated enough product to start and run the phase threes well before those programs get started so.

I think we should be in good shape and capacity I know there's competition for the space that we've been reserving well ahead, and and setting up and we have good relationships with the number of.

The contract manufacturers.

And on cost of goods tolls that there is this quarter, a 1.9 million dollar reserve associated with a lot of products that did not meet our quality standards for that is something specific to this quarter.

Perfect. Thanks.

Thank you and we have your last question coming from the line of Vincent Chen from Bernstein. Please proceed.

Great. Thank you very much for taking the questions bidding in just a couple of them just the first wanted to just slow roasted commercial dynamics. So you're about five to six quarters since the launch as point just opened about the point that growth trajectory from Baird destroyed Thats changed a little since many of the patient suffering kind of waiting start shrug in our pent up demand at launch like there has been on drugs, how should we think about.

Emil D. Kakkis: And on cost of goods sold, there is a $1.9 million reserve associated with a lot of products that did not meet our quality standards, so that is something specific to this quarter. Perfect, thanks. Thank you. We have your last question coming from the line of Vincent Chan from Bernstein. Please proceed. Great. Thank you very much for taking the question and fitting me in. Just a couple of them.

These dynamics with Christiana going forward and how do you think about different patient pool on both the adult and pediatric sides and how far penetrate over into them and what might the supply for trajectory going forward.

And what it would just be a quick one to follow up on the early on manufacturing.

Vincent Chan: I guess the first one is just about the growth of commercial dynamics. So you're about five to six quarters into launch at this point, which is often about the point that growth trajectory for rare disease drugs tends to change a little since many of the patients have been kind of waiting to start the drug and are in pent up demand at launch, and likely are then on drugs. How should we think about these dynamics with CRISPR going forward? And what should we think about different patient pools on both the adult and pediatric sides? And how far penetrated are we into them?

Oh I'm curious about how you could you provide some additional color on how you think about the merits of contract manufacturing versus your own manufacturing as the sort of a broader June 3rd manufacturing landscape evolves going forward.

Okay sure.

Those type of growth above launch.

I think when we we announced start form you are looking at as at summarize numbered through time I think if you. If I showed you the line graph, which I have asked the team to put into our R.R.R.

Deck Fugazy line, I think you'd see that Doesnt really looks like it's flattening, it's a steady course, but.

Emil D. Kakkis: And what might this imply for the trajectory going forward? And then the second one would just be a quick one to follow up on the early manufacturing. I'm curious about how you could provide us with some additional color on how you think about the merits of contract manufacturing versus your own manufacturing as the sort of broader gene therapy manufacturing landscape evolves going forward. Okay, sure. So let's talk about births and bad bloods. I think when we announce starting forms, you're looking at summarized numbers through time. I think if I showed you the line graph, which I've asked the team to put on our deck so you can see the line, I think you would see that it doesn't really look like it's flattening.

It's not the same as it was the first few quarters, where we had the trial patients on where were we definitely at some warehouse station feet lined up and ready to go but we're seeing a pretty steady smooth.

Growth to it so I just think it's not quite as distinctive a change, but it's not unexpected there will be some slowing now what one of our key tenants of the PDL strategy.

Is that we wouldn't run out of docs, let me patients at the doctors were seeing because those patients would those of PDL will be finding new patients that are reps have not gone too. So the idea is to keep the fall full.

With investing essentially as many people finding patients who are doing the sales piece, that's what's unique about the model.

Vincent Chan: It's a steady course, but... I'm sure it's not the same as it was in the first few quarters where we had the trial patients on where we are, and we definitely had some warehouse stations people lined up and ready to go, but we're seeing a pretty steady flow, is that we wouldn't run out of doctors, I mean patients that the doctors were seeing because those patients would, those PDLs would be finding new patients that our reps have not even gone to. So the idea is to keep the funnel full, with investing essentially as many people, finding patients as who are doing the sales piece. That's what's unique about the model.

My hope would be if it works out well that will continue to the growth rate because we keep the funnel for fresh identified patients and doctors and Thats why the subscriber numbers continues to go up as we keep finding those new doctors and getting them prescribing.

That's sort of the way, we see it and I will that graph will be put into our debt can you kind of we've got a maybe a greater few of what it looks like over time, maybe they'll help.

Managed question, we don't want be cage on that as pretty straight forward.

Now on the manufacturing.

Contract manufacturing for simple products is.

Definitely more cost efficient, where you there's a whole bunch of capacity and you can pick and choose US plenty you don't have a hard time getting to a gene therapy has been very competitive. It's also very sophisticated complex manufacturing, which is requires higher standards of performance and people.

Emil D. Kakkis: My hope would be, if it works out well, that we'll continue the growth rate because we keep the funnel full of fresh, identified patients and doctors, and that's why the prescriber number continues to go up as we keep finding those new doctors and getting them prescribing. So that's sort of the way we see it, and that graph will be put into our deck, and you can kind of at least get maybe a greater feel for what it looks like over time, and maybe that'll help. Managed question We don't want to be cagey about that. It's pretty straightforward.

Our contract manufacturers doing fine job. We're moving ahead of the program, but I think in long island for this kind of assisted product. We would expect most companies to go to their own manufacturing plant, where they control the process that can control no no how that will help elevate and improve the productivity the processes and allow them to gain efficiencies.

Vincent Chan: Now on the manufacturing side, Country Manufacturing for Simple Products, definitely more cost efficient, where you have a whole bunch of capacity, and you can pick and choose. There's plenty; you don't have to have a hard time getting to gene therapy has been very competitive. It's also very sophisticated and complex manufacturing, which requires higher standards of performance and people. Our contract manufacturer is doing a fine job, and we're moving ahead with the program. But I think in the long run, for this kind of sophisticated product, we would expect most companies to go to their own manufacturing plant where they control the process. They can control know how that will help elevate and improve productivity, the processes, and allow them to gain efficiencies. And since we have two programs in the clinic, and a third one coming, having our own plant will allow us dramatic efficiencies by being able to run three programs essentially in one plant when that plant goes online. If you're running one at a time, maybe you wouldn't have that efficiency. But we have enough in play to make it worthwhile.

And since we have to pros in the clinic third when coming having our own plant will allow us dramatic efficiencies by number three programs essentially in one plant when that plant with normal online if you're running one at a time it maybe you wouldn't have that efficiency.

But we have enough in play to make it worthwhile, but it takes some time to put a plant together and want to do well.

The contract work in the meantime, but I would say front expenses good product youre, almost always better off from a cost perceptive and the patrol perspective of running year on manufacturing if it's simple manufacturing like that 70.

Contract manufacturing for that batch and tank type thing.

I wouldn't build a plan to do that so many people to can do nice job for you.

Thanks for taking question congrats again.

Good.

Thank you I am showing no further questions at this time I would now like to turn the conference that can is still working.

Emil D. Kakkis: But it takes some time to put a plant together, and you want to do it well. The contract is working in the meantime, but I would say for an expensive, sophisticated product, you're almost always better off from a cost perspective and a control perspective of running your own manufacturing. If it's simple manufacturing, like Metsevi... Contra manufacturing for a fed batch tank type thing, I wouldn't build a plant to do that with so many people that can do a nice job for you.

Okay.

Thank you for joining US today. This concludes our call and a replay will be available and if you have additional questions. Please contact us by phone or at IR and authentic dotcom. Thank you for mining.

Ladies and gentlemen. This concludes today's conference. Thank you for your participation and wonderful. Thank you may now disconnect.

Vincent Chan: Thanks for taking the question and congrats again. Thank you. I am showing no further questions at this time. I would now like to turn the conference back to Ms. Danielle Kittley. Thank you for joining us today. This concludes our call and a replay will be available soon. If you have additional questions, please contact us by phone or at ir at ultragenyx.com. Thank you. Ladies and Gentlemen, this concludes today's conference. Thank you for your participation and have a wonderful day. You may now disconnect. Tazeen Ahmad, Yigal Nochomovitz, Yaron Werber, Gena Wang, Anupam Rama, Emil Kakkis, Yaron Werber, Joseph Schwartz, Emil Kakkis, Laura Chico, Jack Allen, Eric Crombez, Maury Raycroft, Unknown Executive, Unknown Attendee, Huidong Wang, Aaron Olsen, Joori Park, Howard Horns, Ultragenyx Pharmaceutical Inc [inaudible]