Ultragenyx Pharmaceutical Inc. (RARE) Q4 2022 Earnings Call Transcript

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Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE) Q4 2022 Earnings Conference Call February 16, 2023 5:00 PM ET

Company Participants

Joshua Higa - Head of Investor Relations

Emil Kakkis - Founder, President and Chief Executive Officer

Erik Harris - Executive Vice President and Chief Commercial Officer

Camille Bedrosian - Executive Vice President and Chief Medical Officer

Aaron Olson - SVP, Corporate Strategy and Finance

Ted Hazinga - Chief Accounting Officer

Conference Call Participants

Gena Wang - Barclays

Chris Raymond - Piper Sandler

Joon Lee - Truist Securities

Yigal Nochomovitz - Citi Research

Tazeen Ahmad - Bank of America

Jeff Hung - Morgan Stanley

Maury Raycroft - Jefferies LLC

Dae Gon Ha - Stifel

Liisa Bayko - Evercore

Anupam Rama - JPMorgan

Joel Beatty - R W. Baird


Good afternoon, and invited to nan Ultragenyx Fourth Quarter and Full Year 2022 Financial Results Conference Call. [Operator Instructions] It is now my pleasance to move nan telephone complete to Joshua Higa, Executive Director and Head of Investor Relations.

Joshua Higa

Thank you. We person issued a property merchandise detailing our financial results, which you tin find connected our website astatine Joining maine connected this telephone are Emil Kakkis, Chief Executive Officer and President; Erik Harris, Chief Commercial Officer; Camille Bedrosian, Chief Medical Officer; Aaron Olson, Senior Vice President of Corporate Strategy and Finance; and Ted Hazinga, Chief Accounting Officer.

I'd for illustration to punctual everyone that during today's call, we will beryllium making forward-looking statements. These statements are taxable to definite risks and uncertainties, and our existent results whitethorn disagree materially. Please mention to nan consequence factors discussed successful our latest SEC filings.

I'll now move nan telephone complete to Emil.

Emil Kakkis

Thanks, Josh, and bully afternoon, everyone. Some of you whitethorn person listened successful connected my position astatine nan caller JPMorgan Healthcare Conference wherever I talked astir our attraction for areas for 2023. Over past year, we completed respective strategical investments, aligned our teams and resources astir nan highest value-generating programs for nan company. This year, we'll proceed to attraction connected operational ratio while generating information from our cardinal objective programs successful Angelman, osteogenesis imperfecta and our pivotal cistron therapy studies.

In 2022, we generated much than $350 cardinal of world gross successful our 5th twelvemonth arsenic a commercialized company. This year, we expect gross to beryllium successful nan $420 cardinal to $450 cardinal scope from our 4 products crossed 5 indications. We expect a dependable gross maturation to proceed arsenic nan existing products are still successful comparatively early phases of commercialization.

At nan aforesaid time, nan investments made complete nan past fewer years person positioned america to thrust meaningful worth from ample opportunity programs for illustration GTX-102 for Angelman and UX143 for osteogenesis imperfecta, and we person much precocious bolstered our business pinch further strategical steps. Specifically, we secured a licence and collaboration statement to commercialize Evkeeza for objective homozygous familial hypercholesterolemia successful countries extracurricular of nan US, which will leverage our world commercialized infrastructure and capabilities.

We acquired world emergence to UX111 successful AAV cistron therapy for nan curen of Sanfilippo syndrome from Abeona based connected nan spot of nan pivotal marker information and objective information generated successful nan Transfer A study. We besides exercised our action to get GeneTx pursuing interim information from nan Phase I/II of GTX-102 for nan curen of Angelman syndrome nan GeneTx acquisition gives america afloat power complete that program. And we completed nan build-out of our cistron therapy manufacturing works successful Bedford, Massachusetts, which is expected to statesman accumulation this spring.

This installation and our manufacturing capabilities assistance america nan expertise to amended power nan timing, costs and standard of nan accumulation of our cistron therapies, establishing america arsenic a commercial-ready cistron therapy company. We acquired world emergence to UX111 successful AAV cistron therapy for nan curen of Sanfilippo syndrome from Abeona based connected nan spot of nan pivotal marker information and objective information generated successful nan Transfer A study.

We besides exercised our action to get GeneTx pursuing interim information from nan Phase I/II of GTX-102 for nan curen of Angelman syndrome nan GeneTx acquisition gives america afloat power complete that program. And we completed nan build-out of our cistron therapy manufacturing works successful Bedford, Massachusetts, which is expected to statesman accumulation this spring. This installation and our manufacturing capabilities assistance america nan expertise to amended power nan timing, costs and standard of nan accumulation of our cistron therapies, establishing america arsenic a commercial-ready cistron therapy company.

We acquired world emergence to UX111 successful AAV cistron therapy for nan curen of Sanfilippo syndrome from Abeona based connected nan spot of nan pivotal marker information and objective information generated successful nan Transfer A study. We besides exercised our action to get GeneTx pursuing interim information from nan Phase I/II of GTX-102 for nan curen of Angelman syndrome nan GeneTx acquisition gives america afloat power complete that program. And we completed nan build-out of our cistron therapy manufacturing works successful Bedford, Massachusetts, which is expected to statesman accumulation this spring.

This installation and our manufacturing capabilities assistance america nan expertise to amended power nan timing, costs and standard of nan accumulation of our cistron therapies, establishing america arsenic a commercial-ready cistron therapy company. We besides exercised our action to get GeneTx pursuing interim information from nan Phase I/II of GTX-102 for nan curen of Angelman syndrome nan GeneTx acquisition gives america afloat power complete that program. And we completed nan build-out of our cistron therapy manufacturing works successful Bedford, Massachusetts, which is expected to statesman accumulation this spring.

This installation and our manufacturing capabilities assistance america nan expertise to amended power nan timing, costs and standard of nan accumulation of our cistron therapies, establishing america arsenic a commercial-ready cistron therapy company. We besides exercised our action to get GeneTx pursuing interim information from nan Phase I/II of GTX-102 for nan curen of Angelman syndrome nan GeneTx acquisition gives america afloat power complete that program.

And we completed nan build-out of our cistron therapy manufacturing works successful Bedford, Massachusetts, which is expected to statesman accumulation this spring. This installation and our manufacturing capabilities assistance america nan expertise to amended power nan timing, costs and standard of nan accumulation of our cistron therapies, establishing america arsenic a commercial-ready cistron therapy company.

Within our pipeline, we made beardown advancement complete nan past twelvemonth successful summation to progressing our Angelman program. We initiated a pivotal Phase II/III programme for UX143 and OI and person completed enrollment of nan Phase II information of nan study.

We precocious DTX401 successful 2 pivotal Phase III study for GSDIa and person enrolled nan past diligent into nan baseline screening period. We besides initiated a Phase III study of DTX301 successful OTC, wherever we person randomized and dosed nan first diligent successful this study pinch further patients successful nan baseline screening period. And we initiated dose patients successful nan pivotal seamless study of UX701 for Wilson disease.

As a commercialized institution pinch increasing gross successful a divers late-stage objective pipeline, we precocious evaluated ways to amended our operating efficiencies. We will attraction connected leveraging our established world infrastructure actively managing expenses and headcount to thrust worth from nan commercialized launches and execute connected our astir important objective programs.

With that, I'll move nan telephone complete to Erik to supply much specifics connected nan commercialized programs and their successes past year.

Erik Harris

Thank you, Emil, and bully afternoon, everyone. 2022 was an important twelvemonth for nan commercialized and section teams. Across each nan products, they delivered 35% year-over-year maturation overcoming immoderate of nan early challenges presented by nan only ran variant.

Revenue from Crysvita successful our territories grew 34%; Dojolvi grew 41%; and Mepsevii, our ultrarare merchandise grew 29%. The team's efforts are proving uncommon illness products tin make meaningful gross maturation 5-plus years aft launch. 2022 was besides nan first twelvemonth wherever world income of Crysvita exceeded $1 billion.

Crossing nan period we made imaginable done nan Ultragenyx team's efforts that led to astir $700 cardinal successful full merchandise income crossed North America and Latin America and besides nan efforts of cardinal our caring successful Europe and Asia.

Since launching Crysvita successful April 2018, we person established a beardown guidelines of business that we expect will proceed to turn arsenic we modulation nan superior commercialization responsibilities to Kyowa Kirin successful April of this year. In nan U.S., we added astir 110 commencement forms successful nan 4th fourth and astir 90 patients connected reimbursed therapy, on pinch 50 caller unsocial prescribers.

These metrics are nearing their pre-pandemic levels and support nan 26% yearly gross maturation successful this region. This is peculiarly awesome arsenic nan squad has shifted efforts to uncovering adults into harder-to-reach organization clinics wherever much than 50% of our commencement forms are generated.

With mixed Kyowa Kirin and Ultragenyx build teams successful Q4, we person started to scope galore much prescribers successful nan organization and raising consciousness of XLH, which has helped america successful our diligent find efforts. In Latin America, Crysvita continues to grow, supported by further regulatory and reimbursement approvals and besides from dependable request successful nan pediatric and big setting.

We ended 2022 pinch astir 300 patients connected reimbursed therapy successful this region, and we expect this will proceed to turn arsenic much and much prescribers to nan benefits their patients acquisition from Crysvita.

As is communal successful this region, ordering patterns thrust immoderate quarter-to-quarter variability successful revenue, but nan underlying request continues to turn astatine a dependable pace. In 2023, we updated nan regions for which we will rumor Crysvita guidance. This does a amended occupation of representing nan wide scope of Crysvita and nan full gross to Ultragenyx.

At nan opening of nan twelvemonth and reaffirmed today, we issued guidance of $325 cardinal to $340 cardinal for Crysvita successful North America, Latin America and Europe. This is inclusive of each types of revenue, but our profit share, royalty, rate aliases noncash. Compared to 2022 for nan aforesaid regions and types of revenue, this scope represents betwixt 16% and 22% growth.

Turning now to Dojolvi, wherever I'll statesman pinch nan team's activity successful nan U.S. In 2022, we were encouraged by genuinely beardown diligent demand. We ended nan twelvemonth pinch astir 425 completed commencement forms pinch astir 375 patients connected reimbursed therapy. The number of unsocial prescribers continues to grow, now pinch astir 190 wellness attraction providers penning astatine slightest 1 medicine for Dojolvi.

In 2023, we will beryllium focused connected continuing to amended wellness attraction providers connected nan benefits of nan dose titration supported by our objective studies to guarantee patients are capable to execute optimal dose titration. In Europe, request for Dojolvi continues to beryllium led by nan sanction diligent and early entree programs, peculiarly successful France and Italy. We person besides begun to spot requests travel successful from Germany, Austria and definite Middle East countries. In Latin America, we are continuing to activity done nan process, leveraging our existing infrastructure to grow crossed nan region.

In Brazil, Dojolvi is presently approved, and we are moving done nan process to get afloat reimbursement support from nan Ministry of Finance. We besides expect further state regulatory filings successful nan region later this year. Across each regions, we expect 2023 Dojolvi gross to beryllium betwixt $65 cardinal and $75 million, reaffirming nan scope we announced past month.

This represents betwixt 17% and 35% maturation complete 2022. At nan opening of nan year, we besides issued guidance for full revenue, which we are reaffirming today, nan scope of $425 cardinal to $450 cardinal represents 20-plus percent maturation versus 2022. It includes estimates for Crysvita and Dojolvi that I conscionable mentioned and besides includes Mepsevii and Evkeeza.

With that, I'll move nan telephone to Aaron to stock much specifications connected nan financial results for nan quarter.

Aaron Olson

Thanks, Erik. Earlier today, we issued a property merchandise that included financial results for nan quarter, which I will concisely summarize. Company gross for nan 12 months ended December 31, 2022, totaled $363 million, Crysvita gross successful Ultragenyx territories was $258 million, including $215 cardinal successful nan North American profit stock territory and nett merchandise income of $43 cardinal successful different regions.

Total royalty gross related to nan income of Crysvita successful nan European territory $22 million, Dojolvi gross for 2022 was $56 million, Mepsevii gross for nan aforesaid clip play was $21 million. Our full operating expenses for nan twelvemonth ended December 31, 2022, were $1 billion, which included R&D expenses of $706 million, SG&A expenses of $278 cardinal and costs of income of $28 million.

Operating expenses for nan twelvemonth see noncash stock-based compensation disbursal of $130 cardinal and a onetime R&D disbursal of astir $75 cardinal related to our acquisition of GeneTx. For nan twelvemonth ended December 31, 2022, nett nonaccomplishment was $707 cardinal aliases $10.12 per share. We ended nan twelvemonth pinch astir $900 cardinal successful cash, rate equivalents and marketable securities.

In 2023, our nett uses of rate are expected to alteration importantly arsenic we leverage our established infrastructure and proceed to turn nan apical line. This will beryllium enabled by financial discipline, gross maturation and operational attraction connected our late-stage objective portfolio. While these improvements successful nett rate usage will beryllium partially offset by nan information of our Crysvita North America royalty that will now beryllium to our financing partner. We are assured that nan continuing spot of our business fundamentals will let america to thrust towards profitability successful nan coming years.

Now I'll move nan telephone backmost to Emil to publication nan recap nan 2023 objective catalyst.

Emil Kakkis

Thank you, Aaron. I'll summarize nan catalysts from our wide and divers objective portfolio earlier we unfastened up for nan Q&A. Starting pinch UX143 for osteogenesis imperfecta, setrusumab's anti-sclerostin system provides a unsocial dual action to reside nan body's maladaptive consequence to nan bad collagen. If unsocial maximum stimulates much osteoblast to mature into bony making cells and makes those cells summation their bony accumulation while besides limiting bony resorption.

The Phase II information of nan study has been afloat enrolled, and we expect to stock these information successful modulation to nan Phase III successful mid-2023. Separately, we are playing initiate a young pediatric study that compares setrusumab to bisphosphonates to measure full fractures successful a younger diligent population, which person a overmuch higher fracture frequency.

Next, GTX-102 successful Angelman syndrome. We are continuing to spot encouraging signs of objective activity crossed nan patients who person been dosed nether nan amended and expanded entree protocols. We precocious began screening patients successful some description cohorts and expect to supply nan adjacent information update based connected a larger number of patients successful nan programme later this year.

Turning to nan cistron therapy programs. With UX111 for Sanfilippo syndrome, we're expecting to person a gathering pinch FDA successful nan first half of 2023 to talk nan scheme to record for accelerated support based connected a biomarker endpoint. For DTX401 for GSDIa, we enrolled nan past diligent successful nan baseline screening play for nan pivotal study earlier this year. Once this diligent has been dosed, nan 48-week timepiece will begin, we expect to stock this Phase III information successful nan first half of 2024.

DTX301 for OTC deficiency dosed nan first diligent successful nan Phase III study earlier this year, we expect enrollment successful this study will summation momentum arsenic much patients make it done nan baseline screening period. UX701 for Wilson illness enrolling patients successful nan dose-finding stage. We expect to beryllium complete mid-2023 pinch nan information connected information and first signs of objective activity expected successful early 2024.

Finally, UX053, our mRNA programme for GSDIa has completed enrollment successful nan azygous ascending dose cohorts of nan Phase I/II study, and we expect to person these information successful nan first half of 2023. Based connected these analyses and different work, we'll past reappraisal our plans for nan adjacent steps successful nan program.

I founded Ultragenyx successful 2010. 13 years later, we person 4 commercialized products and are approaching gross of $450 million. We besides person 1 of nan astir robust late-stage objective pipelines successful uncommon diseases. We're now poised for nan adjacent shape of nan institution pinch increasing revenues, fueling our improvement of caller pipeline priorities.

In nan coming years, a increasing gross base, financial subject and larger denotation opportunities will let america to scope profitability while besides starring nan early of uncommon illness medicine.

With that, let's move connected to your questions. Operator, please supply nan Q&A instructions.

Question-and-Answer Session


[Operator Instructions] Our first mobility comes from nan statement of Gena Wang from Barclays.

Gena Wang

I will inquire 1 mobility each for Angelman programme and besides osteogenesis imperfecta. For Angelman program, what are nan doses you selected for nan description cohort A and B? And past for nan osteogenesis imperfecta, successful nan midyear update, really would you use, first, tin you punctual america nan 2 doses utilized successful nan evident Phase II portion? And really would you usage nan biomarker consequence alteration mineral density to found those algorithm for Phase III portion?

Emil Kakkis

Great. Thank you, Gena. So successful nan Angelman, we person been, of course, evaluating higher doses and done a dose titration period. We haven't put retired what doses we are using, but we've established immoderate doses that we judge person an due use consequence that we'll beryllium utilizing nan description successful some loading patients and successful their attraction levels. We've put immoderate accusation retired of nan scope of doses that we've been trying, but we'll put retired much accusation erstwhile we person it connected nan nonstop doses we're using.

With respect to osteogenesis imperfecta, we're comparing doses successful some children from ages 5 to adults to 25, and we're comparing 20 to 40. Our anticipation is that nan younger children whitethorn request much supplier successful bid to get capable attraction of antibodies utilizing pharmacokinetic study to execute nan optimal results.

So we'll look astatine nan concentrations of supplier successful nan young and nan old, and we'll besides look astatine nan biomarkers for bony accumulation P1NP, and we'll person besides immoderate bony marl density information arsenic well, and nan extremity is to comparison those and find do we request to usage a higher attraction of supplier successful nan younger patients to execute nan optimal effect aliases not?

So look astatine this arsenic dose tuning alternatively than dose finding. We cognize nan dose. The mobility is do we request to spell a small higher successful nan younger patients and -- you'll get a small publication connected what this supplier does successful young patients astatine that time, which I deliberation will beryllium much responsive patients than nan older patients that person been treated before, astatine slightest our anticipation based connected bony illness we've treated successful nan past.


[Operator Instructions] And our adjacent mobility comes from nan statement of Chris Ramsey from Piper Sandler.

Chris Raymond

Just 1 mobility connected a collaboration that I don't deliberation I've heard you guys talk about. So Enozyme coming mentioned that they conscionable started a collaboration pinch you guys to find misdiagnosed ENPP1 patients. It seems XLH seems to overlap possibly phenotypically pinch that disease. Emil, this plus would look to beryllium thing that would, I would think, fresh successful wrong your wheelhouse developmentally.

Just benignant of funny if you had immoderate thoughts connected this collaboration and possibly immoderate thoughts connected nan supplier itself, particularly successful ray of nan information that these guys had astatine slightest apical statement coming and really you're reasoning astir this narration going forward?

Emil Kakkis

Yes. We activity pinch a batch of companies connected nan rumor of test and not conscionable different companies, we're each trying to thief find patients and stock that accusation pinch each other. At this point, we are not readying connected bringing immoderate much products into our portfolio.

And we proceed to watch nan field, including what Indesign is doing and others pinch respect to caller opportunities for uncommon diseases. But astatine this point, we person connected our sheet each we request to negociate and -- but uncovering patients and moving pinch our partners and others successful nan section is thing we do routinely.


And our adjacent mobility comes from nan statement of Joon Lee from Truist.

Joon Lee

With nan biomarker information for setrusumab, is location a level of bony statement you wouldn't want to exceed. Are location imaginable information issues, peculiarly successful young patients, increasing bones wherever excessively overmuch bony statement could lead to imaginable information issues, possibly proceeding loss, for example.

Emil Kakkis

So nan mobility is whether you tin stimulate excessively overmuch bony maturation and benignant of impinge nerves for illustration successful proceeding aliases otherwise, I deliberation nan truth is these patients are very deficient successful their bony production. So we're starting from a spot of deficiency. And while if you had a familial defect of sclerostin, you mightiness get these problems nan expertise for america to sound down nan level of costs to nan grade required, I think, is very different from a familial deficiency state.

Secondly, I would say, nan patients are opening astatine a position of very deficient bony quantity. As we dainty them and grow, we'll look astatine -- aft we've improved their bony spot astatine a constituent of establishing a attraction dosing. And based connected nan asteroid study wherever we -- nan curen was stopped and we looked astatine resorption, it looks for illustration we tin establish, let's say, little predominant attraction dosing erstwhile we get patients afloat loaded and having their bony spot improved, which I deliberation would mitigate, for example, if location was a semipermanent consequence of that kind.

But let's look it, correct now, these patients are suffering each day. Their bones are disintegrating and that's first bid of business, but we'll ever watch retired for managing nan effect of our narcotics going forward. But astatine this point, we're not concerned astir it successful nan opening of this program.


And our adjacent mobility comes from nan statement of Yigal Nochomovitz from Citi.

Yigal Nochomovitz

So obviously, we are getting a batch of questions lately connected nan OI programme and romo comes up rather a batch successful that conversation, which obviously, arsenic you know, is anti-sclerostin. So if you could thief america pinch nan speedy elevator transportation connected why setrusumab is differentiated from romo, and why your antibody will beryllium nan preferred action perchance NOI?


Emil Kakkis

Sure. First of all, romo was designed and developed for curen of osteoporosis and approved and branded successful that area. What we're going to beryllium doing is dose optimizing for nan osteogenesis imperfecta indication, not nan osteoporosis indication. They person a limit of 12 months of treatment, we will not person that limit. We will beryllium capable to person chronic dosing, which will beryllium very important successful this disease, which is lifelong.

And secondly, by optimizing nan dosing regimen, we'll beryllium capable to dainty patients successful an optimal measurement arsenic a uncommon illness institution will besides beryllium capable to support patients specifically. So nan operation of nan dose, nan regimen and support programs will differentiate setrusumab from what retired location astatine romo correct now. So those are immoderate of nan factors, I think, that will beryllium important.

Yigal Nochomovitz

And conscionable a follow-up connected Gena's earlier mobility regarding nan dose action for nan OI study that you're going to publication retired successful nan mediate of nan year. Once you prime that dose, will that beryllium nan aforesaid dose that is utilized successful nan younger patients successful nan 2 to 5 year-old erstwhile you're comparing head-to-head versus nan post?

Emil Kakkis

Well, if that dose, for example, turns retired to beryllium higher, if 20 isn't nan dose, it needs to beryllium higher, we'll past accommodate that complete to nan different study dose arsenic well. We would expect to.


And our adjacent mobility comes from nan statement of Tazeen Ahmad from Bank of America.

Tazeen Ahmad

Emil, I conscionable wanted to travel up possibly connected nan opportunity successful Sanfilippo syndrome for UX111. Can you conscionable punctual america what nan competitory scenery looks for illustration today? And really galore patients do you deliberation location are successful nan U.S. and abroad. And past a speedy follow-up connected your manufacturing installation connected nan caller one, would that support each of your cistron therapy programs going forward?

Emil Kakkis

Thanks, Tazeen. So pinch Sanfilippo IIIa, 1 of nan decisions we had to make successful picking up nan programme was whether location was a very bully action astir that we could do conscionable arsenic well. And our position was location wasn't really. The different programme successful lifetime, they are really -- they're going retired of business. This merchandise was amended than that product, I think, from a standpoint of biomarker reductions successful effect.

There is simply a lentivirus approach, which I deliberation has its ain challenges, it's reasonably early on. But really, location isn't another, I think, effective AAV cistron therapy retired location that's astatine nan shape that says. So our emotion was that this would beryllium nan lead programme and had nan champion efficacy that I've seen from astatine slightest a biomarker standpoint. So that was our decision.

With respect to nan organization of nan world, there's astir apt a fewer 1000 patients, but nan -- you person to deliberation of this arsenic a small spot much of an incident population, right? Because nan champion effect appears to beryllium successful kids that are nether 2 years old, truthful it was a small spot for illustration Zolgensma, they request to beryllium young to get nan champion use would we dainty older patients, perhaps, it depends connected what happens successful nan regulatory process. I deliberation location whitethorn beryllium use successful older patients, but it's intelligibly nan optimal use happens erstwhile you dainty Young.

So I would look astatine it that way. What I was saying to you astir this cistron therapy and dissimilar immoderate of nan different diseases wherever location are different treatments. If we adhd a cistron therapy that's doing what we judge we spot is doing correct now, we deliberation fundamentally each sample diligent won't want to get treated because nan different options are conscionable nary astatine this constituent successful time. And truthful it has nan benignant of devastating effect that you person pinch SMA, and I deliberation nan take complaint would beryllium very precocious if we tin get it approved promptly.

Now nan different mobility was nan manufacturing works and capacity. The works has 2 suites that tin tally 30 runs a year. One suite is operating correct now. We will -- we tin run a 2nd suite. 30 runs twelvemonth gets a batch of what we request done. I don't cognize that we'll grip 100% of nan needs because it depends connected which programs you're talking astir to execute that.

Our scheme has ever been to person immoderate hybrids, immoderate statement manufacturing and immoderate of our own. And if necessary, we do person a greenish abstraction a greenfield works abstraction adjacent to our works that we could double nan works further. But correct now, I deliberation 30 runs will return america a agelong measurement successful nan future. And if we're astatine that high-level occurrence rate, treating that galore cistron therapies, we tin past put successful expanding that capacity further. But it will return america a agelong measurement for what we request astatine nan moment.


And our adjacent mobility comes from nan statement of Jeff Hung from Morgan Stanley.

Jeff Hung

I conjecture for setrusumab, you talked astir nan 2 doses what benignant of incremental use would you expect aliases want to spot pinch nan 40-milligram per kilogram dose complete nan 20? And past tin you talk astir nan feedback that you've been proceeding connected nan motorboat of Evkeeza successful Europe?

Emil Kakkis

So pinch setrusumab, we haven't group precise criteria. We really want to look astatine nan gradations of supplier attraction and supplier effect arsenic we spell along. But to springiness you a unsmooth idea, if location were -- if doubling nan dose gave you 10% much bony production. I don't deliberation it's worthy it. But if it gave you 50% much bony production, past I would opportunity that's worthy it. So if that gives you benignant of a unsmooth thought I deliberation that would beryllium what we would beryllium looking for is thing much meaningful to warrant spending and giving that overmuch much drug.

With respect to Evkeeza, we've had tremendously affirmative feedback from doctors connected it, some successful Europe and we've had a fewer compassionate usage requests and patients treated. And I deliberation that we're excited astir imaginable successful [indiscernible] really nan first really bully supplier that doesn't dangle connected nan LDL receptor astatine each and tin beryllium fixed conscionable arsenic a monthly IV and -- truthful if we tin get it reimbursed and get entree retired there, I deliberation we will spot a beardown uptick because location is awesome liking successful it. And portion of nan logic we decided to partner pinch Regeneron connected nan programme successful nan first place.


Our adjacent mobility comes from nan statement of Salveen Richter from Goldman Sachs.

Unidentified Analyst

This is Tommy connected for Salveen. So for nan UX053 information coming this year, tin you punctual america what immoderate of nan specifications present are successful position of duration, number of patients and immoderate bars aliases benchmarks wherever you would spot a affirmative signal?

Emil Kakkis

Certainly, nan UX053 programme is an mRNA LNP that's producing this enzyme that will thief reconstruct glycogen metabolism. We'll beryllium looking for changes successful biomarkers and glucose merchandise and biomarkers of glucose fragments that are accumulating arsenic good arsenic information branders astir liver aliases immune response, etcetera. So it will beryllium chiefly a biochemical benignant of look astatine some glucose power arsenic good arsenic merchandise of glycogen fragments.

So those 2 things should thief america get an thought astir dose. These are each single-dose patients that were escalated astatine single-dose ascending dose benignant of cohort. So it will beryllium a first denotation of what we tin execute successful position of metabolic correction based connected -- chiefly biochemical misers.


And our adjacent mobility comes from nan statement of Maury Raycroft from Jefferies.

Maury Raycroft

I was wondering for nan setrusumab Phase II update, tin you explain if you'll person each patients astatine each of nan 2 doses and nan property scope is 5 to 25. But are you breaking retired what proportionality are older versus younger?

Emil Kakkis

Yes. So for -- what we'll person is for those 24 patients will person each their information done astatine slightest 2 months, including nan past patients in. For immoderate of nan patients that were started past twelvemonth will person possibly six months of data, which will see BMDs that were done astatine interim clip points. So that will beryllium benignant of a wide group of data.

We will look astatine different property groups, and we haven't decided really overmuch we request to disclose. We'll person -- we person ages that are distributed astir nan property scope that will let america to look astatine different ages and usage some PK and nan biomarker modeling to effort to find whether we request to summation nan supplier vulnerability astatine nan little doses.


Our adjacent mobility comes from nan statement of Dae Gon Ha from Stifel.

Dae Gon Ha

Maybe a mobility connected GTX-102. Can you possibly supply immoderate updates connected nan scoliosis patient? Has that diligent resolved afloat to proceed receiving nan dose? And immoderate update to nan clip statement of FDA submission of nan package for nan protocol harmonization?

Emil Kakkis

Yes. The patients, arsenic we said before, a resolved fundamentally resolved nan problems they had. I deliberation that we're continuing to evaluating him. He's not redosed yet. We person to hold until his we will hold until his macromolecule levels person resolved, which we will do astatine intervals and measure, but we're encouraged really that's gone and nan 2nd mobility was connected -- yes.

So we're readying that chat shortly, and we'll beryllium presenting really to attack moving up pinch description cohorts successful nan U.S. And we're expecting a bully meeting. We deliberation we've gotten bully responses done discussions pinch them lately and I consciousness for illustration there's an opportunity to move ahead.

But we still request to person that general chat successful bid to unfastened up nan protocol successful nan U.S., which we deliberation will beryllium important successful being capable to quickly grow nan study and put america successful position to get a ample capable magnitude of information to beryllium assured astir designing a Phase III.


And our adjacent mobility comes from nan statement of Liisa Bayko from Evercore.

Liisa Bayko

Could you tally done conscionable pinch nan alteration successful -- to nan royalty. Can you conscionable punctual america of that? And really you're seeing benignant of nan nett profit from that changing is nan royalty somewhat balanced to what you'd beryllium getting from nan profit split, that would beryllium helpful.

Emil Kakkis

Yes. So to beryllium clear, you're talking astir nan move from a profit stock pinch our partner, Kirin to nan royalty period. Is that correct? That's what you're talking about?

Liisa Bayko

Yes. Exactly, yes.

Emil Kakkis

Well, successful general, that crossover will fundamentally beryllium even. There won't beryllium a important change, really. The measurement we system it primitively made was really beautiful good modeled successful position of predicting what our stock should be. So nan 29%, nan apical tier of nan royalty will screen and expect to screen immoderate commercialized costs. We are sharing immoderate costs pinch them.

But astatine this point, if you look astatine nan full image of really nan profit stock was designed and really this is -- it's beautiful flat, beautiful similar. And truthful we consciousness very bully that you wouldn't spot a important measurement disconnected aliases alteration successful nan gross stream. I don't cognize if there's thing more, Aaron, you don't want to opportunity to that.

Emil Kakkis

No, that was good summarized. Thanks, Emil.


[Operator Instructions] Our adjacent mobility comes from nan statement of Anupam Rama from JPMorgan.

Anupam Rama

Two speedy ones from me. Following up connected Tazeen's mobility connected UX111 and MPS III has been gathering pinch nan FDA been calendared? And possibly locomotion america done nan scenarios that could play retired here. And if you are capable to spell pinch an accelerated way guardant for that program, is location immoderate read-through to your broader cistron therapy programs.

And past mobility two, possibly could you grow connected nan connection successful nan property merchandise that pinch GTX-102. There continues to beryllium a dose and time-dependent objective activity successful nan population. And possibly if you could supply immoderate type of colour connected what type of use you're seeing complete what clip period? That would beryllium helpful.

Emil Kakkis

Yes. Normally, pinch regulatory authority discussions, we don't precisely put retired nan nonstop timing of meetings and events that grade nan gathering is set, and we're readying to meet pinch them shortly. But does nan constituent of nan gathering is that nan FDA had already agreed connected a objective endpoint and pinch a longer play of clip to evaluate. However, of late, they person started showing immoderate acceptance of heparan sulfate arsenic that is predictive.

And we judge successful our nationalist chat pinch Peter Marks and successful different settings arsenic nan heparan sulfate marker whitethorn beryllium imaginable arsenic nan primary, which would let america to record earlier than waiting for nan objective data. So our chat will attraction connected tin we usage heparan sulfate of nan peculiar high-quality assay that's being utilized for purposes of filing pinch a committedness to complete nan objective follow-up data, of course, to verify nan objective benefit.

And truthful that will travel comparatively soon. And we'll fto you cognize arsenic soon arsenic we cognize what nan reply is to that question. It doesn't mean nan programme is -- it conscionable intends we tin spell a small faster. If we tin spell faster, it conscionable allows america to record earlier. We still person to group up nan CMC manufacturing pieces of nan program. And we're trying to tally that successful a superior businesslike measurement arsenic imaginable because we do person a batch connected our plate.

So GTX-102, we disclosed that location was immoderate dose and time-dependent differences. We person really mentioned this before. When we put retired accusation earlier, we had talked astir nan truth that nan quantitative endpoints astir nan Bailey were amended pinch nan higher dose groups and pinch nan lowest dose group astatine 2 mg successful nan U.S. So that was nan dose-dependent piece. And we've said that patients look to amended complete time, and that's nan time-dependent piece.

So it's accusation we've been seeing it's successful nan main drivers are nan ones we've already disclosed, which are -- we're talking astir successful nan Bailey scores and connection and sleep. And we're evaluating aggregate things and looking astatine galore things, but we consciousness bully astir nan shape of consequence we're seeing pinch some dose and time-dependent and that's why we're moving into description cohorts.


And our adjacent mobility comes from nan statement of Joel Beatty from R W. Baird.

Joel Beatty

For revenue, are location immoderate seasonal effects from Q4 of past twelvemonth and Q1 of this twelvemonth to beryllium alert of?

Emil Kakkis

Well, location are ever seasonal effects, but I deliberation actually, I deliberation we did good past twelvemonth successful position of hitting our marks. And I'm not judge Aaron would person thing much to say. But I deliberation you tin ever expect immoderate lumpiness peculiarly pinch Latin America because nan orders travel successful burst and disconnected and on. And truthful it's a small spot harder to predict. It's conscionable portion of nan quality of nan uncommon illness business. But I deliberation things are well. Erik, did you person thing other to adhd connected lumpiness?

Erik Harris

You covered it arsenic acold arsenic Latin America is concerned, I mean, I deliberation it's important to admit that we've had dependable maturation complete nan past 5 years for Crysvita. It establishes nan golden modular for curen of XLH and we expect it to proceed to turn arsenic we've seen accordant increases successful cardinal capacity indicators, specified arsenic diligent finding, commencement forms, reimbursed patients and unsocial prescribers.

So request remains strong. That said, we do acquisition immoderate seasonality successful ceasing ordering patterns successful Q4 and Q1, which has been accordant year-over-year, if you look backmost complete nan erstwhile years. Q1 being a small lighter arsenic expected arsenic patients activity done nan reauthorization and changeable security process. So it conscionable takes a small longer connected to get on. But we stay assured successful nan underlying request and which is why we reaffirmed our guidance.


And our adjacent mobility comes from nan statement of Yaron Smith from Cowen.

Unidentified Analyst

This is Brendan [ph] connected for Yaron. Sorry, if you conscionable reply my telephone telephone for conscionable a second. But for Crysvita, I noticed Q4 income really did jump up a bit. I was hoping you tin possibly springiness america immoderate colour arsenic to what was really underlying that conscionable successful Q4 comparative to Q3. And if this is benignant of immoderate trends that you're expecting to clasp guardant clasp moving forward? And past I conscionable wanted to inquire connected Angelman.

I cognize there's a batch of questions present connected dosing and things for illustration this. But tin you conscionable springiness america a consciousness of what we could expect successful nan adjacent time to readout successful position of really really galore patients you're reasoning to see whether they'll see them from nan description cohorts and possibly complete really agelong really benignant of conscionable trying to get a consciousness of wherever nan soul barroom is for you each successful position of erstwhile you want to put retired nan data.

Emil Kakkis

Sure. Well I'll reply nan supplier mobility first. And past maybe, Erik, you tin touch connected nan Crysvita and nan beardown Q4 question. So connected Angelman, we've been releasing. We've been doing these dose titration costs, which were conscionable comparatively mini for diligent groups. But it's clear we request to person thing for illustration astatine slightest 10 patients successful each group to benignant of springiness america nan benignant of information that we tin do statistic connected and astatine slightest do capable projection to understand really to powerfulness a study.

So I'm looking for nan announced to person possibly 20 patients aliases astir half of what we request to enroll. That's giving you a unsmooth idea. And now successful addition, we would person nan patients we've already treated who will person been titrated successful attraction mode, and I would expect that would beryllium nan benignant of measurement of information that would let america to accurately task what Phase III will look like, which is I deliberation what investors inquire for america is to person assured information that will let them to spot nan early for nan programme successful a Phase III program. So that's that. And for Crysvita Q4, I deliberation it's a shape we've seen before, Erik. Perhaps you want to adhd to nan pattern.

Erik Harris

Yes. We had expected a beardown 2nd half of nan twelvemonth arsenic we were hampered successful early 2022 pinch nan Omicron variant. We saw continued summation successful diligent volumes successful nan offices arsenic they opened up much and much arsenic good arsenic information successful unrecorded of acquisition meetings and programs. And I deliberation consistently increasing request passim nan twelvemonth was 1 of nan main factors driving nan beardown Q4.

Emil Kakkis

So it's a spot of a rebound retired of nan hampered first portion of nan year, but it mostly has been beardown successful Q4.


This does reason nan question-and-answer convention of today's program. I'd for illustration to move nan programme backmost to Joshua Higa for immoderate further remarks.

Joshua Higa

Thank you. This concludes today's call. If location are further questions, please interaction america by telephone aliases astatine Thank you for joining us.


Ladies and gentlemen, for your information successful today's conference. This does reason nan program. You whitethorn now disconnect. Good day.

Editor: Naga

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