RARE Ultragenyx Pharmaceutical

Joshua Higa Director, Investor Relations
Emil Kakkis President and CEO
Camille Bedrosian Chief Medical Officer
Erik Harris Chief Commercial Officer
Mardi Dier Chief Financial Officer
Gena Wang Barclays
Tazeen Ahmad Bank of America
Yaron Werber Cowen
Dae Gon Ha Stifel
Yigal Nochomovitz Citigroup
Cory Kasimov JPMorgan
Maury Raycroft Jefferies
Joon Lee Truist Securities
Hannah Latimer Morgan Stanley
Laura Chico Wedbush
Salveen Richter Goldman Sachs
Nicole Gabreski Piper Sandler
Liisa Bayko Evercore ISI
Call transcript

Good day and thank you for standing by. Welcome to the First Quarter 2021 Financial Results and Corporate Update Conference Call. At this time, all participants are in a listen-only mode. After the speakers’ presentation, there will be a question-and-answer session. [Operator Instructions] I would now like to hand the conference over to your speaker today, Joshua Higa. Please go ahead.

Joshua Higa

Thank you. Good afternoon. And welcome to the Ultragenyx financial results and corporate update conference call for the first quarter 2021.

We have issued a press release detailing our financial results, which you can find on our website at I am Joshua Higa, Director of Investor Relations.

Joining me on this call today are Emil Kakkis, Chief Executive Officer and President; Camille Bedrosian, Chief Medical Officer; Erik Harris, Chief Commercial Officer; and Mardi Dier, Chief Financial Officer. I would like to remind investors that this call will include forward-looking statements within the meaning of the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995, including but not limited to, the types of statements identified as forward-looking in our annual report on Form 10-K that was filed on February 12, 2021, our quarterly report on Form 10-Q that will be filed soon and our periodic subsequent reports filed with the SEC, which will all be available in the Investors section on our website. These forward-looking statements represent our views only as of the date of this call and involve substantial risks and uncertainties, including many that are beyond our control. Please note the actual results could differ materially from those projected in any forward-looking statement.

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

Emil Kakkis

Thank you, Josh, and welcome to everyone on the phone.

So far 2021 has been a productive year for Ultragenyx.

We have made great progress towards the initiation of four pivotal clinical studies with novel therapies for rare genetic diseases and a broad portfolio of six clinical stage programs. The clinical progress is complemented by continued advances in our three commercial franchises, marking 2021 as an important inflection point in our growth as a company. Starting with gene therapy, we made significant regulatory and operational advances toward the initiation of the DTX301, DTX401 and UX701 pivotal studies. Most recently, we completed successful regulatory discussions for DTX301, our AAV8 gene therapy for OTC deficiency, as one of the last key steps before initiating that Phase 3 study.

We have also completed all the regulatory discussions for the DTX401 Phase 3 and are working with sites to get the study started soon. Early in the year, we announced that the IND is active for innovative Phase 1, 2, 3 studies for UX701, an AAV9 gene therapy for Wilson disease.

We are currently on track to launch all three of these pivotal studies this year with the GST-1A and Wilson studies on track to begin enrolling early in the second half.

In addition to the late stage gene therapies, we are pushing ahead with UX143, the monoclonal antibody for osteogenesis imperfecta that we recently licensed from Mereo BioPharma.

We are in the planning process for the Phase 2/3 study for this program and we are currently on track to kick off this pivotal study in pediatric patients by the end of the year.

As a reminder, osteogenesis imperfecta is one of the largest groups of rare genetic bone disorders and is an excellent complement to preceded with respect to the clinical and commercial capabilities needed to craft and execute a top notch development and launch plan.

Moving to GTX-102, the antisense oligonucleotide program for Angelman Syndrome.

We are continuing to make progress towards resuming the Phase 1/2 study.

Our goal for the program at this specific time is two-fold.

First, to move forward as quickly as possible restart dosing at the low dose as it showed activity within and visually monitored dose titration plan to assure safety. And second to broaden the scope of the program to allow the program to accelerate once a safe and active dose level has been determined given the strong activity we have seen with the molecules so far. Two of those goals our partner GT Genetics submitted an amendment to the existing approved native filing to initiate study in Canada. Genetics also submitted a new clinical trial application for the second ex-U.S. regulatory agency to open clinical sites outside of the U.S.

We have an encouraging -- we had encouraging discussion with that European regulatory agency regarding GTX-102, including all the detailed efficacy, safety and non-clinical data, along with the same dosing and monitoring plan that was provided to the FDA. European agency agreed in principle with this analysis and plan and a full filing is made on this basis to that agency. Based on this interaction we are confident we can start the study outside the U.S. this year.

Our discussions are continuing with the FDA on removing the clinical hold.

We have submitted additional clinical information requested and a meeting is pending with the FDA. Camille will provide a little more detail on this later in the call. We look forward to providing updates as definitive milestones are made in the Angelman program.

Moving to our newest clinical stage program, UX053 is our mRNA candidate for GSDIII or glycogen storage disease Type III or debrancher deficiency. This is the first clinical program to come out of collaboration with our tourists through which we have rights to 12 programs.

We are working on two other earlier projects in the mRNA space that we will discuss as they mature.

We are always evaluating additional opportunities to harness this promising technology for patients with rare genetic diseases. In the last year Mardi has come forward. It’s not just a theory but a viable strategy based on the highly successful COVID vaccine program and we are also very encouraged with what we see with this technology. UX053 program has free clearance from the FDA to start the Phase 1/2 study in glycogen storage disease Type III or debrancher deficiency. This program will further build on our experience with gene therapy in glycogen storage disease type Ia or von Gierke disease and is expected to start later this year.

Turning to our commercial portfolio, we had a good Q1 that Erik and Mardi will describe further. Crysvita in North America continues to do well now that we are three years into launch, as COIVD restrictions have eased somewhat and clinics further reopened in 2021.

We have seen an increase in diagnosis of XLH patients that we expect to help drive long-term growth for Crysvita.

We have initiated our strength in a number of efforts to support this increased diagnosis in XLH. This includes increasing our digital and social media activities, broadening the set of physicians we meet with and using patient education and genetic counseling to improve diagnosis across a broad family tree. In Latin America the team continues to make good progress in establishing the value of Crysvita for patients with XLH and we continue to see more and more patients winning injunctions to receive reimburse therapy, which has started to generate meaningful revenue.

Turning to Dojolvi, which has been off to a great start. We saw strong demand in the third quarter and fourth quarter of 2020 driven by conversion of 80 clinical trial and existing capacity of these patients and the most severe of diagnosed patients. We see a solid growth rate of new starts going forward and we are encouraged by the great positive feedback we are receiving from prescribers in the U.S. In Europe our discussions with regulators continue. But we are also seeing strong new patient demand for Dojolvi. Recent longer term efficacy data and safety from 1818 patients in France, these are named patient treated patients were published in Ultragenyx and metabolism. Camille will get into the details later in this call. But it’s good to see our Phase 2 data corroborated by an independent French investigative team in their patients in France. I will now hand the call off to Erik to provide more detail on our commercial progress.

Erik Harris

Thank you, Emil, and good afternoon, everyone. In 2020 the commercial team was able to find success in the face of many unprecedented challenges and in the first quarter of 2021 we continue to build on that momentum. I will start with Crysvita.

Our leading indicators including patient times, start forms reimburse patients in the first quarter were strong and we are confident about our trajectory for the rest of the year.

As expected, we did see some seasonality in the first quarter driven by the annual reauthorization process. At this time, we are reaffirming our 2021 guidance for revenue in Ultragenyx territories of $180 million to $190 million. Based on where we finished 2020 this would represent strong growth 30% to 37% year-over-year. In the United States we are continuing to hear positive feedback from the medical and patient communities. Once patients with XLH or TIO start therapy with Crysvita very few discontinue. This is mostly due to the benefits patients are experiencing while receiving Crysvita, as well as the support our patients support services team provides. At this point, three years into launch, we have established strong relationships with all of the major endocrinology and metabolic bone centers.

Solid growth will come from our patient filing efforts in the community clinics where the majority of our new adult star forms originate.

We are increasing investments and successful tactics that we piloted during the pandemic and are modestly expanding our field teams to reach more of those community clinics.

Just a quick comment on the launch of Crysvita for TIO, we continue to see a steady flow of new start forms for patients with this ultra-rare disease. Many of these patients are seeing the same physicians who treat patients with XLH and OI. Over time we expect the launch to continue this trajectory, while leveraging our current field and patient support teams. The demand we are seeing across Latin America for Crysvita remain strong. The base of patients continues to expand as more are granted injunctions, gain access to name patient sales. It is typical within the region, we do expect Latin America ordering patterns to be uneven as our team continues to make significant progress on full reimbursement approval within the region.

Turning now to Dojolvi, which was approved for the treatment of long-chain fatty acid oxidation disorders by the FDA in June 2020 and by Health Canada IN February 2021. In the United States approximately three quarters into the launch almost 10% in February 2021. In the United States approximately three quarters entered the launch, almost 10% of the estimated low end of the range for the prevalent population in the United States have been prescribed Dojolvi. We believe that many of these patients are the most severe phenotypes. We received approximately 230 start forms from approximately 115 unique prescribers of Dojolvi and have approximately 180 patients on reimbursed commercial therapy. This continues to speak to the broad interest we are seeing from the physician community and strong support from payers.

As of the end of March 2021, over 135 million lives in the U.S. have Dojolvi coverage from over 50 policies. Perhaps, as important as this broad coverage, we are seeing the time it takes from receiving a completed start form to a patient beginning reimbursed therapy to be less than 45 days. This is a faster turnaround time than we saw with Crysvita at a similar stage of launch. It is great to see so many of these patients in the U.S. with LC-FAODs successfully navigating their insurance policies. Despite the pandemic and the challenges patients are faced with and trying to get into see their doctor, the launch is exceeding our expectations.

As restrictions continue to ease, we are confident in the current trajectory of new start forms across all three brands of Crysvita, Dojolvi and Mepsevii. With that, I will turn the call over to Mardi to share the financial results.

Mardi Dier

Thanks, Erik. Good afternoon, everyone and thank you for joining today’s call. We issued a press release earlier today that included a financial update, which I will briefly summarize. Company revenue for the quarter ending March 31, 2021, totaled $99.4 million. Crysvita revenue in Ultragenyx territory was $42.1 million, including $36.3 million from North -- from the North America profit share territory and net product sales at $5.9 million in other region. Total royalty revenue related to the sales of Crysvita in the European Territory was $3.9 million.

As Erik alluded to earlier, there are really two factors to keep in mind when looking at the first quarter Crysvita revenue.

First, in the North America profit share territory, we saw the anticipated seasonality from the annual reauthorization process that occurs at the beginning of each year.

We are pleased that the first quarter revenue, the North America profit share territory grew 33% versus the first quarter 2020.

Second, we have received a large order from Brazil’s Ministry of Health towards the end of the quarter that reflects our success in identifying more XLH patients that are able to get reimbursement through the injunction process in Brazil.

As is with the case with Brazil’s Ministry of Health, we expect continued uneven ordering pattern for this territory. The Dojolvi revenue for the quarter was $7 million.

As we have stated before we will not be providing revenue guidance for the Dojolvi in the first quarters of watch. We believe the metrics Erik just discussed better describe the success, we are having that we are seeing in this launch so far. Mepsevii revenue for the quarter -- first quarter of 2021 was $3.6 million.

We expect these revenues may modestly increase over time.

First quarter 2021 revenue also included $42.8 million related to the tech transfer as part of our strategic manufacturing partnership with Daiichi Sankyo around our HeLa PCL and HEK293 technologies. Of the total contract value of approximately$185 million we have recommended close to $132 million to-date. The remaining amount allocated to the intellectual property and tech transfer services most likely will be recognized over the rest of this year and will taper significantly over the next three quarters and as the tech transfer activities wind down.

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

Our total operating expenses for the quarter were $206 million, which includes research and development expenses of $147.5, SG&A expenses of $53.3 million and cost of sales to $5.2 million. The R&D cost in the first quarter of 2021 included the $50 million upfront payment for the closing of the Mereo license and collaboration agreement.

As a reminder, we expect our R&D costs this year to increase as we will support the three pivotal gene therapy clinical trials, the UX143 Phase 2/3 clinical study and osteogenesis imperfect and the Phase 1/2 study for the most advanced mRNA program UX053 and GSDIII, and a number of other preclinical activities as we get ready to advance the next program into the clinic.

We also expect SG&A to modestly increase over 2021 as we continue to support the expansion and launches of Crysvita, Dojolvi and Mepsevii.

For the quarter ended March 31, 2021, net loss was $126.1 million or $2.03 per share. This compares to a net loss for the same period in 2020 of $119 million or $2.05 per share. The net loss for the first quarter 2021 includes the $50 upfront payment Mereo and $20.6 million decrease in the fair value of investments and equity securities. Net cash used in operations for the quarter was $153 -- $159.3 million, which includes the upcoming payment to Mereo, as compared to the $95.2 million for the same period in 2020. We ended the quarter with over $1 billion in cash, cash equivalents and marketable securities. This puts us in a strong capital position to reach key clinical and commercial milestones as we continue executing our development and commercial strategies.

Now I will let Camille touch on some of our clinical programs.

Camille Bedrosian

Thank you, Mardi, and I too wish everyone good afternoon. I would like to start by providing a regulatory update on GTX-102, which is being developed with our partner GeneTx for the treatment of Angelman syndrome. Angelman syndrome is a devastating neurogenetic disorder with a broad spectrum of disease manifestations, including speech and cognitive impairment, ataxia or balance issues, growth and fine motor dysfunction, sleep dysfunction and seizures. Late year we reported positive efficacy data from the first five patients treated in the Phase 1/2 study that indicated substantial improvements and multiple remains in all patients.

We also reported all five patients had a grade one or two serious adverse event of lower extremity weakness that now has fully resolved. We paused dosing and enrollment at the first presentation of the event. In support of resuming the clinical study, we have provided the FDA with additional non-clinical data showing the effects of DTX-102 in non-human primates models at single and repeat doses at levels far exceeding an equivalent dose that would be expected to be used in our clinical program. The delayed onset weakness we saw in the Phase 1/2 was not observed in the non-human primates with single doses as high as 10 milligrams or 110 milligram human equivalent dose, nor was it observed with seven monthly doses of 4 milligrams or an equivalent cumulative dose in humans of 314 milligrams.

Importantly, we did see a strong knockdown of the UBE3A antisense at very low monthly doses beginning at 1 milligram or approximately 10 milligram dose equivalent in humans.

We also saw a measurable though not a strong effect at 0.5 milligrams dosed monthly. We recently requested a meeting with the FDA following multiple submissions of substantial non-clinical and clinical data including data confirming that the serious adverse event in the previously treated patients has fully reversed. This meeting has been granted for later this quarter.

Following the meeting, we hope to have fully satisfied the FDA’s questions around me SAE and to have approval to resume dosing in patients in the U.S.

Now I’d like to shift to our strategy outside of the U.S. Earlier this year we held a pre-application meeting with a National Regulatory Authority in Europe, where we presented detailed safety, efficacy and non-clinical information about GTX-102. The authorities agreed in principle on the expansion of the trial to Europe using a proposed modified study design dosing and administration strategy pending review of the application. The application to enroll clinical studies in this country was recently submitted. Separately, we also recently submitted an amended dataset and protocol to the Canadian authority in order to begin enrolling patients there. This submission is currently being reviewed by Health Canada.

Our modification to the study protocol included an amended administration and dose titration plan. Trendelenburg and an artificial CSF flush should help reduce the local contact time and help the ASO reach the cisterna magna as it is diluted and circulation distributed to the brain. Patients will be divided into two starting dose cohorts based on age. Those under eight years old will receive a starting dose of 3.3 milligrams while those eight years and older will start at 5 milligrams. Titration to higher doses will be evaluated on an individual basis after several repeat doses have been administered. This new dosing plan is within the observed range of clinical and non-clinical activity, but below the doses associated with SAE. With this three-pronged approach we feel confident we will be able to resume this important study and share additional clinical data before the end of this year.

Turning now to DTX401 our gene therapy for the treatment of glycogen storage disease Type 1A or GSD1a. We previously completed the scientific advice process with the European Medicines Agency and held the end of Phase 2 meeting with the FDA.

Following these regulatory discussions, we submitted the study protocol two months ago to the FDA.

As of this call, the FDA has not provided any objections to starting the study.

While we await some informal feedback from the agency, we simultaneously are moving forward with steady startup.

As we finalize timing of IRB submissions and approvals, we expect the study to be up and running soon, and anticipate dosing the first patients in the early part of the second half of this year.

Next, I will turn to DTX301 our gene therapy for the treatment of ornithine transcarbamylase or OTC deficiency. At the end of the first quarter, we held a successful end of Phase 2 meeting with the FDA and together with feedback from EMA we now have a finalized Phase 3 study design and end points. The study will enroll approximately 50 patients ages 12 years and older. Patients will be randomized one-to-one to either DTX301 or placebo. The dose of 1.7 times 10 to the 13 genome copies per kilogram defined by the digital drop assay is the same dose that we study in the third and fourth cohorts of the Phase 1/2 study.

For the Phase 3 study we will have co-primary endpoints.

The first is obtained in 24 hour plasma ammonia levels and the second co-primary is a percentage of patients who achieve a response, which we measure by 50% or more discontinuation or reduction in baseline disease management. We did lengthen the Phase 3 duration slightly 48 weeks to 64 weeks to allow more time for patients to be weaned off of their ammonia scavenger medications and protein restricted diets. From our experience with the Phase 1/2 study, we know that it can take some time to establish normal ammonia metabolism and to be able to safely reduce baseline treatment. By moving to 64 weeks, we expect there will be enough time to assure success in the baseline treatment reduction co-primary endpoint and still proceed to development as rapidly as possible.

With the finalization of the Phase 3 design that incorporates feedback from both FDA and EMA, we are rapidly moving forward toward initiation of the study in the second half of this year.

Lastly, I’d like to touch on data that were recently published in Molecular Genetics and Metabolism that describe the clinical outcomes of 18 pediatric and adult patients with long-chain fatty acid oxidation disorders or LC-FAOD, who were treated with Dojolvi or triheptanoin for a median duration of 22 months. In this paper, 18 early access French cases show that triheptanoin reduced the need for medical intervention. Patients in this cohort will follow for a range of nine to 228 months. Similar to the published Dojolvi Phase 2 data, the cumulative annual number of days of emergency home care was reduced from a total of 286 days to 51 days during the 12 months on therapy. Notably, 13 of these patients required zero days of emergency home care during this time. Other reported clinical improvements include a reduced fatigue and myalgia, and elimination of the need for wheelchair use in five of the six patients who had required it in the year prior to receiving triheptanoin.

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

Emil Kakkis

Thanks, Camille. After completing four approvals in our first 10 years, we built out our pipeline of Ultragenyx in last few years to put us in position to have both a full pipeline of late stage assets and multiple products in launch mode. Result varies one [ph] of the broadest and most diverse portfolios in the rare disease space. A clinical pipeline now includes six programs. It is well-balanced across modes, encompassing gene therapies and antibody and antisense oligonucleotide and mRNA. It includes smaller rare diseases where we are essentially the only drug development, but also includes more competitive and much larger opportunities.

Over the long-term, we will continue the strategy of using our insights in relationships and rare disease defined in advance, a diverse set of compelling opportunities.

We will focus more to our efforts now on executing on the new studies and data readouts that we have laid out for 2021 and beyond.

Now, with that, let’s move on to the Q&A portion of the call. Operator, please provide instructions for asking questions.


Thank you. [Operator Instructions] Your first question comes from the line of Joseph Schwartz from SVB Leerink.

Your line is now open.

Unidentified Analyst

Hi. [Inaudible] dialing in for Joe. Thank you for taking our questions. My question is on DTX301 for OTC deficiency. Typically, you have a co-primary endpoint. It can be analyzed several different ways. Usually you have to hit both endpoints, but sometimes you can just hit one of the two or the hurdle can be higher for one over the other endpoint.

So I was just wondering if you could discuss the statistics for your Phase 3 study.

Emil Kakkis


So we are expecting to have hit both endpoints. The ammonia control is easy. But I think the question with the responder and also we think is the clinical meaningfulness of the results. And the clinical maintenance we think is quite dependent on being able to get off of existing therapies.

So if we control ammonia, but can’t get people up there it doesn’t mean much. But our view would be based on everything we have seen so far that if we control ammonia, maintain the ammonia get it below a certain level, we will be able to reduce our diet and drug.

So we feel confident in putting both endpoints forward.

Unidentified Analyst

Okay. Great. Thank you. And then, how are you defining responder. I know that for the in your opening remarks you mentioned 50% plus reduction in the baseline disease management. But I guess I am curious about the ammonia component, are you assuming is there a threshold you have to meet or are you trying to get the patients down to the normal range?

Emil Kakkis

Now the ammonia analysis is really a continuous variable reduction in ammonia level.

So, it is not a responder determined analysis for ammonia. And since we will let relax the entry criteria from ammonia we have seen very sharp declines in ammonia. We would expect a spread of ammonia levels across a range and we expect that variation to compress among patients are treated.

So it’s a continuous variable ammonia level.

You measure not a responder. In the diet -- in the reduction in care, this issue of threshold you could think of it is if you have 50%, we will say, if you get off your scavenger drugs but not relax your diet. That would be 50% reduction in your care sitting of the scavenger drugs and diet.

If you get off both, that’s 100%.

If you get off one, it’s 50%. And the way the responder analysis will go as will count 50% that is getting off the drug the lung will count as a response for that endpoint and getting up everything will count as a complete responder and it would be 100%.

And so we will look at the percent reduction in response in treatment requirement.

Unidentified Analyst

Okay. Great. Thank you so much.


Next question comes from the line of Gena Wang from Barclays.

Your line is now open.

Gena Wang

Thank you for taking my questions. I have two regarding the Angelman. One is for the U.S. and one is for the ex-U.S.

For the U.S., since FDA didn’t ask you for additional animal data and you submitted additional clinical data.

Just wondering what could hold FDA back at your second quarter meeting? And then for the ex-U.S. both Europe and Canada a pending review, will you be able to start dosing in first half this year? And I think you mentioned that we will have some patient data by the end of this year? Can you elaborate a little bit what kind of data will be shared by the end of this year?

Emil Kakkis

Very good. I will go ahead and answer that.

So, on the first part, the Angelman. They asked for more data on the individual patients that were treated and had the event mainly to assess their complete reversal and we have done some additional things and showed they are completely reversed. The question is what can hold them up. We think we have given them enough to get forward.

So I am not sure what else would hold them up. But I think we are being responsive to their requests and we hope that we will move forward. But I don’t have in my head right now what would be the reason not to go ahead.

However that said, we also know that sometimes you can’t predict what regulatory authorities will do and we have initiated work to also initiate in the study ex-U.S. What we said today is that, one ex-U.S. authority said, agreed with the plan given the knowledge about the serious adverse event and the efficacy and everything, agreed with our plan to move forward the same plan we have submitted to FDA. Canadian authorities have seen that now, we are waiting for their response. The timing of those responses from the authorities will determine the timing when we can get going. If they were happened within a shorter period time we could get going, if they take their full period required we may not dose there in the first half. It’s hard to know.

With the U.S., of course, it’s depending on the response we could dose.

Now what we have said in the release though is that, given what we know now about the ex-U.S. path, the one way or another we will have some data in some patients this year and that’s the point we are making for everyone Gena, but you can’t precisely say how those although we are going to play out as they undergo three different regulatory authorities are looking at reviews.

Gena Wang

Okay. And then what kind of data will be shared?

Emil Kakkis

Well, we are talking about the first patients re-dosing again at the going through month -- since they are dosing once a month, we would expect to have several months of dosing on a set of patients. At first our plan currently that would re-posing is called patients six below age eight or six above.

And so we have been looking for some fraction of patients be treated at least a few times. Based on our response we have seen before that within one or two more doses we started seeing things.

And so we think within the timeframe of three or four doses we would have the opportunity to see if we are seeing the clinical fact and whether we are getting the adverse effect. It wouldn’t be definitive information but at least tell you are we dosing is it safe and are we seeing some activity and that’s the kind of range will give you a sense of where we are going.


Next question comes from the line of Tazeen Ahmad from Bank of America.

Your line is now open.

Tazeen Ahmad

Hi. Good afternoon. Thanks for taking my question.

As it relates to Angelman and I guess when would you need to start resumption of the study this year in order to meet your targeted goal of having some clinical data available on patients by the end of this calendar year? And as it relates to the safety profile of the drug, is that kind of a make or break situation based on any discussions that you have had with the agency? And the reason I am asking is Angelman is an area of undermet need.

If you are showing efficacy in these patients, what is the tolerance do you think at the agency and/or physicians would have to -- a safety profile that might not be 100% clean? Thank you.

Emil Kakkis


So, on the -- when started our expectations we need to get started either late this half or early next half in order to have a few least a few doses of in a number of patients, right, before the end of the year.

So we would have to be late this half early next half in order to accumulate enough data. Whatever data we -- we are going to say is, whatever data we have we will put out and we will update on that information.

However, many patients how work much time, so we will commit to doing that. With regard to the safety profile, we think that having low extremity weakness wouldn’t be a good profile to have for a chronic treatment like this.

So, well, clearly, we believe we can get past that because it’s not a drug pharmacologic effect, it’s like a local irritation and inflammation effect which is something should be very manageable.

So we are confident we can get past that. And even so if once we know that an ASO can have this kind of effect, there are many avenues ahead of us even if this all ago, we had to change it we could we could of course use.

So now that we are in this space and we have this ability to change clinical future of an engagement, it’s something worth fighting for and we will fight for getting this done with a drug that gives patients an important efficacy and a safety that’s appropriate and I don’t think having lower extremity weaknesses is acceptable as a long-term safety outcome.

Tazeen Ahmad

Okay. Thank you. And maybe a quick question on Wilson.

You are expected to start your study in the second half of this year. How big of a study do you plan on this being given that you are describing it as a single protocol Phase 1 through Phase 3 study?

Emil Kakkis


So the Wilson Phase 3 study is like a Phase 1/2 study bolted on to a Phase 3 study just to be most accurate. The seamlessness is we don’t go back to regulatory authorities between the decision makings all preset.

So the way it’s going to go as we are doing cohorts in Stage 1 cohorts at three different dose levels in sequence. They are randomized with a placebo group and those cohorts will be six and three.

So there will be a total of 27 patients in that.

The second half of the study is on the order of 60 to 70 patients at this point in time, that’s our expectation.

Tazeen Ahmad

Okay. Thank you.


Next question comes from the line of Yaron Werber from Cowen.

Your line is now.

Yaron Werber

Great. Thanks for taking my question.

So I got two questions for you if you don’t mind. One is do you have a sense, do you ask -- they want to actually see the weakness recapitulated in animal models for them and to show resolution for them to move forward or is that not one of the things because it’s hard to recapitulate that? I am trying to get a sense what would get them comfortable?

Emil Kakkis


Yaron Werber

And then, secondly, when you look at the structure, this is a cyclic base a gap, right? So the chemistry is a little different from SPINRAZA and how valid is the chemistry? Thank you.

Emil Kakkis

Well, the FDA has not asked us to recreate anything in animals frankly at all and they do not ask us to do any more work. They recognize we have used higher dose in animals and for many repeated doses with very high load and not seen it.

So, it’s clearly not a toxicity of this all oligo. This oligo is not shown be toxin on non-human primates and so I think that’s really important.

Now, what I else can say with regard to the chemistry is that LNAs can have toxicities, but this particular oligo does not have toxicities that we see in the pathology of the non-human primates given repeat doses.

So we feel comfortable while the chemistry is being appropriate. I do think the ability of ASOs to cause irritation or injury is not unknown, it’s not new. It’s been seen, there’s been high protein in the CSF in a number of ASO programs including the recent HD1.

I think the key here is what’s the therapeutic index, how much efficacy do you get for the dose and in this case we have -- with this LNA extraordinarily potent LNA drug that is actually achieving -- beginning to achieve efficacy in the 3 milligram to 10 milligram range.

So, a very potent and we think at that range we can avoid those secondary contact necessity issues.

I think that’s a distinct advantage of the -- based on the true high potency of this particular one.

So, right now we are comfortable with the chemistry. We think it’s -- particular choices made were very potent.

We are aware of a lot of variations that we have made and others have made. Dr. Dindot has done some exceptionally high quality work in this field.

So we feel good about where we are at. And we are, of course -- we are also looking at making small variations that might change the profile, but we feel pretty good about the successity in efficacy we are seeing and right now the FDA is just weighing more confirmation about the clinical situation and have not asked for any other animal data from us.

Yaron Werber

With them which is the long-term follow clinically and how do you control the risk mitigation. Is that what it is?

Emil Kakkis

No. They just want a more definitive proof that the patients didn’t have any residual neurological effects. Because I think this is a benefit risk question. They are trying to assess if they put more patients at risk. Will they have an irreversible harm from that, right? That is fundamental.

We have said no. They just wanted further information to confirm that that’s true. And we have good reason to believe it’s not because we don’t think it’s a direct neurotoxicity issue.

I think it’s just neuro inflammation issue. And it resolved -- the majority effect resolved within a few weeks.

And so they just wanted more definitive quantitative measures that help prove that they are reversed. And we have done those measures including MRIs and more lumbar punctures, as well as special neurophysiological tests and it found the patients are normal.

Yaron Werber

Great. Thank you.


Next question comes from the line of Dae Gon Ha from Stifel.

Your line is now open.

Dae Gon Ha

Good afternoon. Thanks for taking the question. Emil, maybe I will just touch on one more Angelman question.

So recognizing you have three parallel paths with the ex-U.S. sites, as well as the U.S. I was wondering if you can comment on potential alignment between the three regulatory discussions. I mean do you see a lot of concordance between the three or do you see quite a bit of disparity in terms of what they are requesting? And then second question is more commercial, I was wondering perhaps it’s for Eric.

Given that U.S. has been easing up you in your prepared remarks talked about the irregular ordering patterns in LatAm. But now COVID also seems to be somewhat more rampant in the ex-U.S. site.

So I was wondering what you guys are currently seeing on that development front? Thanks.

Emil Kakkis

Very good. Thanks for the question Dae Gon. I will let Eric in a moment. He can talk about COVID around the world. Eric, so prepare for that. I will do the first part.

So one of the great techniques in rare disease regulatory is to exploit the actual differences between regulatory authorities and find the best answer somewhere in order to move forward. And that is extremely important part of moving very complex diseases forward in the drug development.

So it’s very often that we will go to another authority in order to get started and to get going and have involved in three programs that did that. In the end all came back to the U.S., all got approved in the U.S.

So it’s just a normal thing. We don’t really look for concordancy.

We are proposing ex-U.S. the same study in the same design.

We have not had any negative feedback from the other European Authority, does not give us any changes to the protocol that we were fundamental. Whatever the Canadians are seeing are actually in line with what we submitted to our other European.

So that’s the same and we don’t have any further feedback.

With the FDA right now we are highly focusing in on the current five patients and reducing them and just getting their understanding about doing that piece. And by limiting the scope we think will give us an opportunity to kind of generate a little bit of a more narrow and safe path for getting started in the U.S. on the existing five patients.

So that’s our approach right now.

So let me hand this off now to Erik to talk little about, I think, the question was Erik on COVID maybe easing up in the U.S., but how is COVID affecting South America?

Erik Harris

Yeah. A couple of things I will point out.

First, when you consider 2020 we put out our guidance in advance of the COVID pandemic and we ended up in the upper end. That’s because the team did a great job of adapting to the situation and maintaining the same level of engagement with both physicians and patients for virtual and digital means.

So we have learned a lot in 2020 and we will continue to leverage those successful tactics as we move into 2021, which is why we have taken into account our abilities to operate in this pandemic environment, as well as the potential for -- high potential for easing of restrictions throughout the year across the globe. That having been said, no doubt the situation varies region-by-region and in some instances, country-by-country and the LatAm team has done a great job just as the U.S. team has done in adapting to this situation.

So we feel confident that with our projections as we move forward.

Dae Gon Ha

Okay. Thanks.

Emil Kakkis

Thanks, Erik.

We are getting obviously -- we are receiving orders -- we have received orders from Brazil despite the pandemic. I know Brazil has been hard hit. And there’s no doubt it’s going to put pressure on the world, including Latin America, but patients with these disease are also in severe need and so we are pleased to see some ordering continuing. And I think your team just like in U.S. will do all the work to make sure that plays out right.

Dae Gon Ha

Great. Thanks for the clarity.


Next question comes from the line of Yigal Nochomovitz from Citigroup.

Your line is now open.

Yigal Nochomovitz

Hi, Emil and team. Thank you for taking the questions. Could you expand a bit on why you opted for a single seamless protocol for Wilson’s disease or expanding the Phase 1 to Phase 2? Just curious is there something specific about Wilson disease that’s better suited to doing a seamless protocol versus separate protocols?

Emil Kakkis

Well, yes, there are some very distinct differences to Wilson. Number one, it’s been well-studied, well-treated, so they are actually well-established endpoints, which we could define and choose up front.

So, urinary copper excretion, which is a measure of how much copper is essentially dumping out in your urine where it’s not supposed to be is a relatively good measure whether your copper is being rounded to the correct place. Since that’s well accepted in Wilson, we are able to get agreement with authorities on that as a primary endpoint.

So, I think it’s the issue the endpoints being defined and studies before it allows us to pick endpoints right up front.

Secondly, our experience in doing gene therapy of the liver now and two other programs gives us confidence in the dosing range you would like to hit, right? So, we are confident what the dosing range would likely need to be. And then we can hit that range in our Phase 1/2 trial and be able to pick three doses confidently.

So, given that experience liver gene therapy ability to pick doses and endpoints that we can get agreement on then the only thing we need to decide with FDA is how big this study is and how long they are. And with that, all the decisions required to go from Phase 2 to Phase 3 are done.

We will do the Phase 1/2.

We will look at the dose data.

We will pick the dose and we will begin enrolling Phase 3 without having to go back to the authorities will have pre-defined administrative criteria to make those choices.

You can’t do this kind of thing is a disease that’s never been studied with no history of endpoints, right? And where you don’t know the dosing response, right? So, it is not something you can do with most programs, but in this case being a bigger disease with a lot of history we have an opportunity to take advantage of that and do something that would be smoother and faster.

Yigal Nochomovitz

That makes a lot of sense. And then I had one other question on the French study that Camille described. I was really intrigued by the upper end of the cited range of median follow-up of 228 months because that would imply 19 years of follow-up.

So I want to make sure I am understanding that correctly and if so that this study of triheptanoin is actually been running for almost two decades?

Emil Kakkis

Camille, do you want to answer that?

Camille Bedrosian

Yeah. Sure. Thank you. Thank you for the question. Yes.

You are correct.

In fact before Ultragenyx took on the development program for triheptanoin or Dojolvi, the program was being studied by academics for a dozen years or so before that time and even before that.

So you are correct. And physicians even then understood the biochemistry and the metabolisms and the potential for triheptanoin.

Yigal Nochomovitz

All right. Thank you very much.


Next question comes from the line of Cory Kasimov from JPMorgan.

Your line is now open.

Cory Kasimov

Hey. Good afternoon, guys. Thanks for taking the question. Two from me as well.

First one on DTX301, just wanted to ask again about the rationale of going from 48 to 604 four weeks for the endpoint, so patients can win off of prior therapies. Does that -- I am -- I guess, I am curious if that was driven by you or by regulators and if there was anything you saw in the Phase 1/2 data that led you to think this additional time could be beneficial? And then I have a follow-up on Angelman.

Emil Kakkis

Well, the debate with the regulators like it has been for a number of programs both not ours at all of them out there is whether you should be studying these diseases for up to two years, right, in Phase 3. We didn’t feel that was necessary.

And so in the discussion of time we were agreeing to add another quarter, another 12 weeks essentially to the plan. If we are now going to include an endpoint, which result, which required the titration or maximal titration of the drugs and diet. What we saw in Phase 1/2 is some patients responded a little later like say six months or so, which would leave a little less time, if they responded in the ix weeks to 12 weeks as a few did. Then we would have enough time. But if they respond at six months then you are giving them a little less time to titrate their drugs down and die down.

You don’t want to be doing it precipitously, right? You want to do it steadily and to verify that they are not having problems with their ammonia.

So just another few weeks would help us and also manage regulatory desire for a longer study without taking it out two years. We get a little benefit to us in terms of that endpoint and we manage the FDA’s desire for the length of study.

Cory Kasimov

Okay. That makes sense. And then just to go back to Angelman for a second, I just want to make sure I understand. When you restart this program, how should we be thinking about the accrual strategy in terms of whether you would enroll one patient, treat them and then watch and wait before enrolling another or will it happen at a faster pace than that?

Emil Kakkis

Well, there is a staging strategy proposed. There’s two younger ones, two older ones that would get a few doses and if they are okay then we enroll the rest of the two cohorts.

So there’s some staging for two and two and then moving up to what was a total of six and six patients to get through the four doses.

So that’s a stage a little bit that would slow up the enrollment of the second group. But we would have four patients that we think will reasonable short period of time to get started and then be able to expand that to total of 12. If the 12 was good then we have the option in their protocol to expand -- to include another 40 patients at the dose now that appears to be sufficient to have efficacy and also appears to be safe.

So that would give us a lot more data than to learn more about the particular dose that we have hit with our first 12 patients.

Cory Kasimov

Okay. Makes sense. Very helpful. Thank you, Emil.


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

Your line is now open.

Maury Raycroft

Hi, everyone. Thanks for taking my questions.

First one is on Angelman.

I think you mentioned on the 4Q call that the five Angelman patients were losing efficacy benefit after being off treatment. Can you confirm if the five patients fully reverted on efficacy and could this loss of benefit factor into your discussion with FDA?

Emil Kakkis


So, patients have lost a lot of benefit.

I think there may have been some that still retaining a little bit of the words that they gained. But it’s clearly substantially resolved at this point and reversed.

So, yes, it’s been a factor in our discussion with agency, because the effects were not subtle. They were life changing.

So we hope to make that part of the whole benefit risk assessment question. If we can show them the risk of a reversal change is really not there that it is reversible than I think we can open the door to seeing that patient and losing efficacy is not great. I do think the FDA is always first rules about no doing no harm and safety.

So, if we can demonstrate that then I think the efficacy story becomes relevant.

Maury Raycroft

Got it. That’s helpful. And then, one quick one. Yeah.

I think you mentioned potential for an Angelman publication from Scott Dindot’s lab and I am just wondering if you have a status update on that?

Emil Kakkis

I don’t have an immediate update on it. I thought it was submitted. It’s a tour de force of research by the way just, so it’s one of those special like very large papers. That requires a special journal.

So I think it’s still in review and I don’t have an update at this point in time. But it is truly exciting and I think actually redefines the whole Angelman biology a little more clearly, a little more precisely, which is what led into the discovery of the right place to knock down the antisense.

Maury Raycroft

Got it.

Okay. Thank you for taking my questions.


The next question comes from the line Joon Lee from Truist Securities.

Your line is now open.

Joon Lee

Hi. Thanks for taking my questions and congrats on the progress.

For GSDIII why have we decided on mRNA as opposed to DNA DTX301 and DTX401 and I have a follow-up question.

Emil Kakkis

Yeah. There’s a good reason for it.

I think GSDIII is a debrancher deficiency. It’s a very complex large enzyme, has two activities. It wouldn’t fit normally inside an AVV vector. It’s too large.

The second thing that’s unique about GSDIII is that you are creating a limit dextran like a little piece of glycogen that’s leftover when the enzyme doesn’t work. That is actually toxic and you accumulate then every single liver cell. And since gene therapy very often won’t hit every single liver cell you will still have the problem if you hit 10% or 15% of the liver. They have a lot of liver that’s not detoxified, right? Because there’s a cytoplasmic enzyme.

So the advantage mRNA then is twofold, one it conclude a larger protein as we need it here and secondly we have shown a very nice delivery to essentially every parasite and clear it. The last thing I will note this becomes is that storage toxic effect if you clear the toxic dextran it could take some months to accumulate.

So the actual dosing frequency could not be given let say by the loss of the enzyme but the time it takes for toxin accumulation of dextran to occur.

And so we think those are some features that make gene therapy challenging, but maybe for mRNA maybe a better opportunity and that’s why we have gone ahead with mRNA for that indication.

Joon Lee

Got it. And for GTX-102, Angelman, there are several players now following your strategy of stopping the stop. And then Roche, I think has a study up and running, and I think they have advanced two additional doses. Does that play a factor in FDA’s decision and what can we learn from that, I’d be curious if what’s the latest advance from Roche?

Emil Kakkis

Yeah. Well, I haven’t seen Roche put out any information on their trials. I can’t really comment on it. I don’t think the FDA makes a decision between program winners or losers based on early data, that’s not their role. Their role is to look at your program, should you be treating.

If you are asking, well if they have another win, if they can get treated some other way that’s safer. If it was an approved treatment, I would say that may be a factor, right? If they have an approved treatment that works very well and yours is not working and causing safety problems, there is a difference. But in this case it’s not approved and nor have we heard any efficacy of the drug working. We believe we are in a much more potent area and based on the non-clinical data put out, we think our molecule is much more potent than there.

So, if anything I would expect them to have more risk of safety issues than we did.

So, we will see what happens, but I don’t think it’s a factor right now it’s all up to us and GTX-102.

Joon Lee

Got it. And one more if I can squeeze in -- it seems like so they are all targeting the same gene. But you mentioned something about your drug targeting all the splice isoforms or more thorough suppression of the NK cells that are transcribed. Can you -- is that an IP strategy or -- and can you talk to that differentiation between other -- multiple other players in the same thing, but it appears to be the same thing, but maybe a little differently.

Emil Kakkis

No. They are targeting -- trying to targeting antisense but they are targeting a different patented region.

So, the generics team and Scott Dindot have patented region near five prime end of the antisense message that is not covered by the Roche patent, right? The Roche patent is further 3 time downstream, that region is unique and that region for some reason was not included in the Roche patent.

So it is unique exclusive intellectual property about the use of oligo’s within that region the target the antisense. The key value that uniqueness is the fact that it’s way more potent and potency is involved in knocking down all the isoforms, which were not fully recognized by everyone, they were -- people think of this as a single antisense message and what Scott’s work showed.

In fact that there’s a number of antisense molecules and some of them are spliced. And therefore how you pick your targeting may be in the antisense or it may not be in picking toward the five prime he found a particularly unique potency there and that is patented.

So I do think we have intellectual property position on a superior insight in the message. And honestly that’s why we did the deal with genetics. We did the deal because as we told our team it wasn’t really wanted to get in a foot race or a muscle match with Roche or Biogen Ionis, those are big players here so play.

So the question is, was there a scientific insight that gave us an edge.

So, I think, Scott Dindot had the insight and genetics had the rights to it.

Joon Lee

Yeah. Thank you.


Next question is from Jeff Hung from Morgan Stanley.

Your line is now open.

Hannah Latimer

Hi, guys. This is Hannah on for Jeff. What -- for setrusumab, is there a particular profile of OI patients within the pediatric population that you guys think would best respond? And then what do you see is likely the key differences between potential pivotal studies within the pediatrics and adults and perhaps beyond the primary endpoint. Thanks.

Emil Kakkis

Great. All right. Right now to answering that question, we really focus on pediatric pivotal study as kind of the core drivers of the application. The pediatric patients have the highest unmet need. They are the core of the driver. What we will do to cover adults may depend a little on what we see there. But the pediatric Phase 3 is really our core focus. With regard to the profile, if you look across the data that you have now in adults and peds, you see bone marrow density improvements, potential improvements in both OI TYPE I, Type III and Type IV. We know Type IIIs and Type IVs will have more fractures and then Type I it is more severe in general. What we will focus on in this study is patients who have a lot of fractures and this is because they have the unmet need and obviously it’s part of our rare formula and rules that you have to treat sick people with drugs.

And so in this case we will focus on patients who have had more fractures. Bones are more in need of improved strength which is where setrusumab can be very beneficial in terms of enhancing in animal bone activity, increasing bone density but not just any bone density. Bone density in the places require increased strength and that the way that bone is directed would allow us and I think to strengthen bone is certainly in animal models allows a mutant college in animal model to achieve their normal strength after setrusumab.

So we are anti-sclerostin antibody.

So we are -- we are focused on high fracture patients [inaudible] and demonstrating that bone marrow density and fracture improvement can occur with that core data.

We will leverage that to adults for which we already have good data of 90 patients showing it does depend on improvements in bone mineral density in a number of locations in those patients.


Next question is from Laura Chico from Wedbush.

Your line is now open.

Laura Chico

Hi. Good afternoon. Thanks for taking my question. I have one on UX701. I am just wondering if you could comment a little bit on who might be appropriate candidate for gene therapies and I guess I asked this in the context of one, your observational study in Wilson’s disease, if there’s any learnings there? But then also AstraZeneca and Alexion has expanded enrollment in their studies, so just thinking about the impact on your efforts? Thanks very much.

Emil Kakkis

Well, we are -- there’s obviously a lot of people in the space, Wilson, right now, the Alexion, as well as Pfizer with that, but there’s also a lot of Wilson patients. The trial will take more stable patients in the beginning patients, because we haven’t established the safety, but we are looking ultimately for patients who have enough significant illness to measure with the disease. And we are not particularly restricting for example the CNS or other types of manifestations, but we are accepting people who have seen this manifestation. And after the first stage, we will accept people that have some level of liver injury within their certain bounds. We don’t want to take people who are in very severe late stage kind of liver problems, because we don’t -- the gene therapy can have an impact on the liver. But those kind of patients is something we want to look at after the study.

So we -- people who have figured out some measure, but not so sick with the liver, the gene therapy might harm them. And we looked to see both liver manifestations, as well as CNS manifestations in some patients have signs of efficacy in the endpoints with evaluating the program.


Next question is from Salveen Richter from Goldman Sachs.

Your line is now open.

Salveen Richter

Good afternoon. Thanks for taking my questions. On Angelman you mentioned potential variations to the program. It maybe, what are those and what are your updated thoughts on the age factor? And then just the second question in therapy addition, so just give us an update there?

Emil Kakkis


So on Angelman ex-U.S. there are no previously treated patients who were focused on treating naïve patients in the protocols for Canada and the other country are basically based on treating naïve patients at the low dose in the regimen. In the U.S. we are focusing the program now on retrieving existing patients. If that is okay then with the FDA we would move to adding more patients at the point of time when it makes sense. That all the programs we hope would converge at some point on a larger Phase 2 cohort. But right now we are focusing U.S. on retreating the five and ex-U.S. and treating naïve and then eventually will expand.

So that’s the difference we are talking about. The age factor is an important one.

I think from the beginning of Angelman the science and analysis there was a sense that only young patients would respond and there was many people thing that need to be very young patients. That’s based on mouse data. But one of the important things is mice are not people. Mice live only two years.

So humans have to live decades and our brains are just different for that reason.

So I wasn’t so surprised that our brains have to continue to evolve and improve with our life.

So we have observed already is the two youngest patients had the most potent effect of the treatment that we saw. They all said the stronger side effect. The older patients took a little longer and had to get a little higher dose before they saw the effect. But they clearly did have an effect including teenagers.

So the fact you do a teenager I would say was completely unexpected by many people in fact denied that it would happen and I just believe in human neurology, you need to have an open mind of what can really happen, because honestly one thinks they know, but they don’t know.

So you got to do the experiments that’s why we strongly believe in Phase 2 studies that have wider criteria let yourself worn and not prejudge who is going to respond and who won’t respond because you will be surprised sometimes.

So, we think a wide age range can respond, can adults respond, potentially it might be slower, it might be different, but we think there is room for improvement across a range of Angelman patients. We still believe that young patients will probably have a more potent effect than we will see in older patients, but the fact that all respond I think is important. But finally in Duchenne we are making progress with our partner [inaudible] and we have been making constricts successfully and designed and finalized constricts and are doing the work and creating manufacturing system, which is all going well and so we are on track and we will provide an update later in the year about where we are at on the manufacturing of the new strategy and any other work we will have put together. But so far it’s gone very well, very good collaborative teams and the constrict creation has occurred and we are moving forward on our on our vector production.


Next question is from Chris Raymond from Piper Sandler.

Your line is now open.

Nicole Gabreski

Hi. This is Nicole Gabreski on for Chris. Thanks for taking the question.

So, just one on UX053. I know you are on track to start the study in the second half of this year, but just kind of curious going back to your 2019 R&D Day you attend a lot of data around UX053 and we are projecting to file to IND in 2020. I guess can you just talk a little bit about the path for getting UX053 into the clinic. Was there something specific that was gating for that program. And I just -- I guess given your comments to-date that you have two other programs in the mRNA space under development, are there any learnings that you might be able to apply to these future programs?

Emil Kakkis

Sure. Well, 2020 was a difficult year, obviously.

So running a lot of non-clinical things and other things were definitely impaired, our ability to operate were little impaired.

And so, the nonclinical pre-IND stage programs were difficult to move ahead at the same pace. We tried to keep our main clinical programs operating, some of the non-clinical ones had to take whatever time they had to take.

So, it was kind of normal. There certainly was learning though.

One of things we learned is optimizing production of mRNA for these longer mRNAs we are using for translation like of a very large protein.

So, we have been doing a lot of work in optimizing and producing mRNAs that are low -- have low immune stimulating capacity and the team has done a dramatic job actually in improving the cost of manufacturing and the scale of manufacturing.

And so those are a feature that would help us in our other programs for sure.

We have also improved on scaling, making the LNPs for this particular LNP, for this particular canin lupid [ph] and that information also will be very useful in the other programs.

So, I would -- we looked at this first program was putting all the effort into developing it, getting it ready, but to do the second and the third one, I think it’s going to be substantially easier given that all our other technology have been figured out.

And so we decide to put all our effort on one program at the first, get it approved and get into clinic and then we can open the door on bringing other ones forward.


Next question comes from the line of Liisa Bayko from Evercore ISI.

Your line is now open.

Liisa Bayko


Just two quick questions.

First on Angelman, does the FDA, excuse me, sorry, if I apologize, if you answer this before I hopped on late, but is FDA viewing for any additional clinical data generated from other regions before kind of allowing the process to reinstates here, are you -- is there anything along those lines you should be thinking about?

Emil Kakkis

Well, first of all, the FDA would never say that. It said now we are Americans are too precious. Go tested on some foreigners and then come back, they would never say -- that’s not their view. They are looking us in our view. The reality is this is something that happens because they are being conservative we are moving it elsewhere.

As I have said I have been involved in the molecular program, the CLN2 and Medsavy [ph] which actually started actually ex-U.S. because of various questions that couldn’t get answered in a timely way and we went ex-U.S. and then came back to U.S.

So it’s -- there’s nothing there about that. They are not waiting for the others to do it. That may be what happens but they certainly are not and would never ask something like that. They just want to look at what’s going on. I really think their issue is irreversibility and reversibility. It’s really a big deal.

I think they feel like this is a reversal problem then they feel they are taking less risk. But they wouldn’t want to be…

Liisa Bayko


Emil Kakkis

… irreversible damage to some kids, right? That’s their main issue which we get and we think we have to show them that...

Liisa Bayko


Emil Kakkis

… that’s not happening.

Liisa Bayko

All right. That makes sense. Thank you. And then on DMD and gene therapy, I think Pfizer made an interesting announcement saying that it’s taking them a little longer to get their pivotal study up and running due to some I think requirements for additional testing and whatnot. Can you maybe just kind of speak to how you see the opportunity for DMD in the context of development as opposed to leading companies Sarepta and also Pfizer and how that makes you think about your own program and what you need to do and sort of what the opportunity else coming up later to the game, but.

Emil Kakkis

Right. Well, first I wouldn’t consider this a horse race.

We are not racing. If it was a horse race it’s like a 10 mile course is not your 2 to a mile a quarter. But in that context, we are sea biscuit, right, because they are going to come in at the end. But the truth is all approaches are different. And ultimately, our efficacy and safety will win the day. And for us we think we have some advantages, because we can scale manufacturing which will produce a higher quality product really with the HeLa platform at a higher dose at a lower cost. That allows us to do a lot more competitive and to produce really a hybrid.

I think the quality of product is starting to matter how well full it is with the presence of trace plasmid in it or other things. We get a much higher quality product out of the HeLa process we believe and that will what I think make the difference. Combined with other things we are planning to do, we think we can achieve potency equal or greater and also scale and costs that will be much improved and therefore come in the long run as a better product profile.

I think the Pfizer Duchenne announcement related to the potency assay, which has been the bane of existence for many gene therapy programs and the FDA rightly so is concerned about potency variations in manufacturing runs and wants a very high quality thorough activity based protein potency assay from gene therapy products. In other programs, we have resorted to using in vivo assays for that purpose, while we still further developed in vitro. But we have had to have those assays in place as well for our three programs. In Duchenne is tricky because of the nature of the protein improving its activity.

And so it’s not surprising to see some challenges in developing an activity assay for a structural protein.

So well I think it does tell you that the path is rocky but the importance of this treatment can’t be underestimated.

So that’s why so many people are trying to work and solve it and I think microdystrophin as strategy I think it’s real. The data are strong and I am very -- I am very excited to be part of that race because I think we do have some new things to offer and the patients deserve to have every possible path going forward to them as rapidly as possible and not just four year old to seven year old, all the kids with Duchenne and not just U.S. patients but elsewhere as well.

Liisa Bayko

Thank you.


There are no further questions at this time.

Let me turn the call over back to Joshua Higa.

Joshua Higa

Thank you. This concludes today’s call.

For additional questions please contact us by phone or at Thank you for joining us.


This concludes today’s conference call. Thank you all for your participation.

You may now disconnect.