What changed in this filing

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Item 1. Business

2021-02-12 compared with 2020-02-14 · 293 added, 218 removed, 460 unchanged (53% of the section changed)

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For this reason, we are passionate about developing these therapies with the utmost urgency and care.

We were founded in April 2010 by our current President and Chief Executive Officer, Emil Kakkis, M.D., Ph.D., and we have since assembled an experienced team with extensive rare disease drug development and commercialization capabilities.

We were founded in April 2010 by our President and Chief Executive Officer, Emil Kakkis, M.D., Ph.D., and we have since assembled an experienced team with extensive rare disease drug development and commercialization capabilities.

The critical components of our business strategy include the following:

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We generally intend to retain global commercialization rights to our products and product candidates whenever possible to maximize the potential value of our product portfolio.

We do not currently intend to invest significant capital in basic research, which can be expensive and time-consuming.

Focus on excellent, rapid, and efficient clinical and regulatory execution on multiple programs in parallel.

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Approved Products and Clinical Product Candidates

Our current approved products and clinical-stage pipeline consist of three product categories:

biologics, small molecules, and gene therapy product candidates.

We have two commercially approved products, Crysvita® (burosumab) for the treatment of X-linked hypophosphatemia, or XLH, and Mepsevii ® (vestronidase alfa) for the treatment of mucopolysaccharidosis VII, or MPSVII or Sly Syndrome, and three additional product candidates in the clinical pipeline.

Our current approved therapies and clinical-stage pipeline consist of four product categories:

biologics, small molecules, gene therapy, and nucleic acid product candidates.

We have three commercially approved products, Crysvita® (burosumab) for the treatment of X-linked hypophosphatemia, or XLH, and tumor-induced osteomalacia, or TIO, Mepsevii ® (vestronidase alfa) for the treatment of mucopolysaccharidosis VII, or MPSVII or Sly Syndrome, and Dojolvi ® (triheptanoin) for the treatment of long-chain fatty acid oxidation disorders, or LC-FAOD, and we anticipate having six product candidates in the clinical pipeline in 2021.

The following table summarizes our approved products and clinical product candidate pipeline:

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Crysvita for the treatment of XLH

Crysvita is an antibody administered via subcutaneous injection that targets fibroblast growth factor 23, or FGF23, developed for the treatment of XLH, a rare, hereditary, progressive and lifelong musculoskeletal disorder characterized by renal phosphate wasting caused by excess FGF23 production.

Crysvita is an antibody administered via subcutaneous injection that targets fibroblast growth factor 23 (FGF23), developed for the treatment of XLH, a rare, hereditary, progressive and lifelong musculoskeletal disorder characterized by renal phosphate wasting caused by excess FGF23 production.

There are approximately 48,000 patients with XLH in the developed world, including approximately 36,000 adults and 12,000 children.

Crysvita is the only approved treatment that addresses the underlying cause of XLH.

Crysvita is approved in the United States for the treatment of XLH in adult and pediatric patients six months of age and older, and in Canada for the treatment of XLH in adult and pediatric patients one year of age and older.

In the European Union, or the EU, and the United Kingdom, Crysvita is conditionally approved for the treatment of XLH with radiographic evidence of bone disease in children one year of age and older and adolescents with growing skeletons.

A filing to expand the label to include adults with XLH was submitted in November 2019 by our partner, Kyowa Kirin International, or Kyowa Kirin, in the EU and the United Kingdom.

In Brazil, Crysvita is approved for treatment of XLH in adult and pediatric patients one year of age and older.

Crysvita is approved in the United States and Canada for the treatment of XLH in adult and pediatric patients six months of age and older.

In the European Union, or the EU, and the United Kingdom, Crysvita is approved for the treatment of XLH with radiographic evidence of bone disease in children one year of age and older, adolescents, and adults.

In Brazil and Mexico, Crysvita is approved for treatment of XLH in adult and pediatric patients one year of age and older.

We have submitted regulatory filings in various other Latin American countries.

We are collaborating with Kyowa Kirin Co., Ltd., or KKC (formerly Kyowa Hakko Kirin Co., Ltd., or KHK), and Kyowa Kirin, a wholly owned subsidiary of KKC, on the development and commercialization of Crysvita globally.

In September 2019, we announced that the U.S.

Food and Drug Administration, or FDA, approved a label expansion for Crysvita.

The label was updated to include new clinical data demonstrating superiority of treatment with Crysvita versus oral phosphate and active vitamin D (conventional therapy) in pediatric patients with XLH, and improvement in stiffness and maintenance of efficacy of Crysvita in adult patients with longer-term treatment.

The indication was also expanded to include infants as young as six months of age.

In December 2019, we sold to Royalty Pharma for $320.0 million our royalty interest in Crysvita in the European territory (defined below), where it is being commercialized by KKC.

Mepsevii for the treatment of MPS VII

Mepsevii is an intravenous, or IV, enzyme replacement therapy, developed for the treatment of Mucopolysaccharidosis VII, also known as MPS VII or Sly syndrome, a rare lysosomal storage disease that often leads to multi-organ dysfunction, pervasive skeletal disease, and death.

MPS VII is one of the rarest MPS disorders, affecting an estimated 200 patients in the developed world.

Mepsevii is approved in the United States for the treatment of children and adults with MPS VII.

In the EU and the United Kingdom , Mepsevii

is approved under exceptional circumstances for the treatment of non-neurological manifestations of MPS VII for patients of all ages.

In Brazil, Mepsevii is approved for the treatment of MPS VII for patients of all ages

Please see “—License and Collaboration Agreements—Approved Products—Saint Louis University” for a description of our license agreement with Saint Louis University.

Clinical Product Candidates

Crysvita for the treatment of tumor-induced osteomalacia, or TIO

We are also developing Crysvita for the treatment of TIO.

TIO results from typically benign tumors that produce excess levels of FGF23, which can lead to severe hypophosphatemia, osteomalacia, bone fractures, fatigue, bone and muscle pain, and muscle weakness.

Tumor-induced osteomalacia (TIO) results from typically benign tumors that produce excess levels of FGF23, which can lead to severe hypophosphatemia, osteomalacia, bone fractures, fatigue, bone and muscle pain, and muscle weakness.

There are cases in which resection of the tumor is not feasible or recurrence of the tumor occurs after resection.

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There are approximately 2,000 to 4,000 patients with TIO in the developed world.

In October 2018, we presented positive 48-week and 72-week data from an ongoing Phase 2 study of Crysvita in adults with TIO syndrome at the American Society for Bone and Mineral Research 2018 Annual Meeting in Montreal.

In adults with TIO, Crysvita was associated with increases in serum phosphorous and 1,25(OH)2D;

improvement in osteomalacia;

improvement in mobility and vitality;

and reductions in fatigue.

In December 2019, we submitted an sBLA to the FDA for Crysvita for the treatment of FGF23-related hypophosphatemia associated with phosphaturic mesenchymal tumors, or tumor-induced osteomalacia or TIO, which cannot be curatively resected or localized.

We expect to hear back from FDA on submission acceptance and review designation in February 2020.

In June 2020, we and Kyowa Kirin announced the FDA approval of Crysvita for the treatment of FGF23-related hypophosphatemia TIO associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adults and pediatric patients 2 years of age and older.

Please see “—License and Collaboration Agreements—Approved Products—Kyowa Hakko Kirin” for a description of our collaboration and license agreement with KKC.

UX007 for the treatment of Long Chain Fatty-Acid Oxidation Disorders, or LC-FAOD

UX007 is a synthetic triglyceride with a specifically designed chemical composition being studied for the treatment of LC-FAOD, which is a set of rare metabolic diseases that prevents the conversion of fat into energy and can cause low blood sugar, muscle rupture, and heart and liver disease.

There are currently no approved drugs or treatments specifically for LC-FAOD.

The current standard of care for LC-FAOD includes diligent prevention of fasting combined with the use of low-fat/high-carbohydrate diets, carnitine supplementation in some cases, and medium even-chain triglyceride oil supplementation.

Despite management with the current standard of care, many patients continue to suffer significant morbidities and mortality.

Mepsevii for the treatment of MPS VII

MPS VII is one of the rarest MPS disorders, affecting an estimated 200 patients in the developed world.

Mepsevii is approved in the United States for the treatment of children and adults with MPS VII.

In the EU and the United Kingdom , Mepsevii is approved under exceptional circumstances for the treatment of non-neurological manifestations of MPS VII for patients of all ages.

In Brazil and Mexico, Mepsevii is approved for the treatment of MPS VII for patients of all ages.

Please see “—License and Collaboration Agreements—Approved Products—Saint Louis University” for a description of our license agreement with Saint Louis University.

Dojolvi for the treatment of LC-FAOD

Dojolvi is a highly purified, synthetic, 7-carbon fatty acid triglyceride specifically designed to provide medium-chain, odd-carbon fatty acids as an energy source and metabolite replacement for people with long-chain fatty acid oxidation disorders, or LC-FAOD, which is a set of rare metabolic diseases that prevents the conversion of fat into energy and can cause low blood sugar, muscle rupture, and heart and liver disease.

Dojolvi is the first FDA-approved therapy as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed LC-FAOD and the product is commercially available in the United States.

We have submitted Dojolvi to the Brazilian Health Regulatory Agency (ANVISA) seeking marketing authorization.

In Canada, we have been granted priority review and have filed a new drug submission.

Discussions with EU regulatory authorities are ongoing.

There are approximately 8,000 to 14,000 patients in the developed world with LC-FAOD.

In January 2019, we announced positive topline data from the ongoing long-term extension study of UX007 in patients with LC-FAOD, demonstrating sustained reductions in the duration and frequency of MCEs and a long-term safety profile similar to what has previously been seen with UX007.

A total of 75 patients are enrolled in the study including 24 patients who were previously enrolled in the company-sponsored Phase 2 study, 20 naïve patients who had not previously been treated with UX007 and 31 patients from expanded access or investigator-sponsored studies.

Patients who previously completed the Phase 2 company-sponsored study and rolled over to the extension study received treatment for an additional 78 weeks.

The median annualized MCE and duration rates during the extension treatment period were zero.

Over the entire treatment period, patients had a 67 percent reduction in median annualized event rate and a 66 percent reduction in the median annualized duration rate.

Patients who were naïve to UX007 at study entry have received up to 78 weeks of treatment.

These patients have demonstrated a 70 percent reduction in the median annualized event rate (2.3 events/year pre-UX007 to 0.7 events/year during extension study treatment period) and an 80 percent reduction in the median annualized duration rate (10.0 days/year pre-UX007 treatment to 2.0 days/year during extension study treatment period).

Overall, the safety profile observed in the long-term extension study was consistent with what has been previously observed with UX007.

The most common treatment-related adverse events were diarrhea, vomiting, and abdominal pain.

One patient discontinued due to a treatment-related adverse event.

There were two deaths during the extension study, both deemed to be related to disease progression and not due to treatment with UX007.

One of these patients was naïve to UX007 and one was previously in an investigator-sponsored study.

Both patients had Trifunctional Protein (TFP) Deficiency type LC-FAOD, a type known to have a high mortality rate, and both had experienced severe disease manifestations when initiating UX007 treatment in the extension study.

In October 2019, we announced that the FDA accepted our NDA for UX007 for the treatment of LC-FAOD.

The FDA assigned a PDUFA date of July 31, 2020.

An Advisory Committee meeting is not expected at this time.

The NDA filing is supported by a comprehensive package of data including results from a Company-sponsored Phase 2 study of UX007 in 29 patients, a long-term safety and efficacy extension study in 75 patients including 20 patients who were previously naïve to UX007, a retrospective medical record review of 20 original compassionate use patients, 67 patients treated through expanded access, and a randomized controlled investigator-sponsored study of 32 patients showing an effect on cardiac function.

We have also submitted an application to regulatory authorities in Brazil, and we have initiated discussions with other regulatory authorities in the EU and the United Kingdom and Canada.

Please see “—License and Collaboration Agreements—Clinical Product Candidates—Baylor Research Institute” for a description of our license agreement with Baylor Research Institute.

Clinical Product Candidates

DTX401 for the treatment of glycogen storage disease type Ia, or GSDIa

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DTX401 has been granted Orphan Drug Designation in both the United States and in the EU and the United Kingdom , Regenerative Medicine Advanced Therapy (RMAT) designation and Fast Track designation in the United States.

In January 2019, we announced positive topline data from the first dose cohort (n=3, dose of 2.0 x 10^12 GC/kg) of the Phase 1/2 study of DTX401 in GSDIa.

All three patients in Cohort 1 demonstrated clinically meaningful improvements in glucose control shown by time to hypoglycemia and reductions in cornstarch requirements.

In September 2019, we announced positive data from the second dose cohort (n=3, dose of 2.0 x 10^12 GC/kg) of the ongoing Phase 1/2 study of DTX401.

All three patients in Cohort 2 showed a clinical response with improvements in glucose control and other metabolic parameters compared to baseline, and all three patients in Cohort 1 continued to demonstrate long-term, durable responses.

All patients demonstrated increases in time to hypoglycemia compared to baseline during a controlled-fasting challenge, normalization of daily glucose levels which has allowed for clinically significant reductions in the amount of cornstarch, and meaningful improvements in assessments including lower lactate levels after treatment and early reductions in liver fat fraction.

As of the data cutoff date of August 31, 2019, there have been no infusion-related adverse events and no treatment-related serious adverse events reported.

All adverse events have been Grade 1 or 2.

Four of the six patients in Cohorts 1 and 2 had mild, asymptomatic elevations in alanine aminotransferase (ALT), similar to what has been observed in other programs using AAV-based gene therapy, and were successfully treated with a reactive tapering course of steroids.

Based on these results, we proceeded to a confirmatory expansion cohort of three additional patients at the second cohort dose of 6.0 × 10^12 GC/kg.

All three patients have been dosed and data from the expansion cohort are expected in the first half of 2020.

If the expansion cohort results are consistent with those observed to date, then the Phase 3 trial expected to begin in 2020 would study this dose level.

In May 2020, we announced positive data from the confirmatory cohort in the ongoing Phase 1/2 study at the American Society of Gene & Cell Therapy (ASGCT) annual meeting.

The data demonstrated increased time to hypoglycemia and substantial reductions in cornstarch usage.

Across all three cohorts in the study, 100 percent of patients had demonstrated meaningful and sustained cornstarch regimens over time and significant increases in time to hypoglycemia.

At the data cut-off on April 23, 2020 , four of six patients in the first two cohorts had discontinued daytime cornstarch.

In January 2021, we announced positive longer-term safety and efficacy data from the first three cohorts of the ongoing Phase 1/2 study.

All nine patients continued to demonstrate improved glucose control while tapering or discontinuing oral glucose replacement with cornstarch and improvements in energy metabolism pathways over the long term.

At the primary evaluation timepoint at Week 52, the overall mean reduction in cornstarch was 77% across all three cohorts, including two patients in Cohort 3 showing a reduction of greater than 75%.

Follow-up for more than two years for the three patients in Cohort 1 have shown sustained and continued cornstarch reductions with a mean reduction of 91% through weeks 104 and 120.

In Cohort 3, d ata collected from continuous glucose monitoring (CGM) indicate d that glycemic control was maintained and even improved despite the reductions in cornstarch dependence.

T hese reductions in cornstarch dosing have had an impact on energy metabolism and body weight.

Seven of nine treated patients had decreases of 5% (5.6 kg) to 21% (10.5 kg) in bodyweight following DTX401 treatment, with a mean decrease of 12% from the mean baseline weight of 82.8 kg in these seven patients.

The notable weight loss was attributed to improved glycemic control and potentially increased physical activity reported by patients.

All three patients in a fourth and final Phase 1/2 cohort, which utilized prophylactic steroids, had been dosed at the same dose as Cohorts 2 and 3.

Through 11 weeks post-dosing, there had been no treatment related serious adverse events and all three patients were doing well, demonstrating early reduction in daily cornstarch intake.

We have completed Scientific Advice with the EMA and had an End of Phase 2 (EOP2) meeting with the FDA to discuss the Phase 2 data, the Phase 3 design, and endpoints.

Based in part on this feedback, we currently plan to conduct a 48-week Phase 3 study in approximately 50 patients, randomized 1:1 to DTX401 dosed at 1.0 x 10^13 GG/kg, as calculated using a new droplet digital PCR (ddPCR) test method, or placebo.

All patients in the study are expected to cross over to the therapeutic arm and receive therapy at the end of the initial 48-week follow-up period.

Based on the regulatory discussion and pending finalization with the regulatory authorities, we currently intend to study as primary endpoints glycemic control by assessing the maintenance of glucose control by CGM and the reduction in cornstarch requirements.

These primary endpoints are expected to be supported by key secondary endpoints of improvement in percent of time spent in normal glucose control (60-120 mg/dL), time to hypoglycemia in controlled fasting challenge, and the GSDIa functional assessment diary signs and symptom scale.

The durability of the treatment would then be supported by the longer-term Phase 1/2 data and early treated Phase 3 patients.

Based on the results to date, the therapeutic benefit appears to increase over time during the second year after treatment.

We currently expect to initiate the Phase 3 study in the first half of 2021.

Please see “—License and Collaboration Agreements—Clinical Product Candidates—REGENXBIO Inc.” for a description of our license agreement with REGENXBIO Inc.

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DTX301 has received Orphan Drug Designation in both the United States and in the EU and the United Kingdom and Fast Track Designation in the United States.

In January 2020, we announced data from the third dose cohort and longer-term data from the first two dose cohorts of the Phase 1/2 study of DTX301.

The data demonstrated that up to six of the nine patients demonstrated a response as of the data cutoff date of December 9, 2019.

In Cohort 3 (n=3, dose of 1.0 × 10^13 GC/kg), there were two confirmed female responders as well a third potential male responder who requires longer-term follow-up to confirm response status.

In Cohort 2 (n=3, dose of 6.0 × 10^12 GC/kg), one female patient newly demonstrated a response starting at Week 52 which was confirmed at Week 78.

Two previously disclosed responders in Cohort 1 (n=3, dose of 2.0 × 10^12 GC/kg) and Cohort 2 have remained clinically and metabolically stable at 104 and 78 weeks, respectively.

As of the data cutoff date, there have been no infusion-related adverse events and no treatment-related serious adverse events reported in the study.

All adverse events have been Grade 1 or 2.

All three patients in Cohort 3 had mild, clinically asymptomatic elevations in ALT levels, similar to what has been observed in other programs using AAV-based gene therapy.

All three patients have been responding to reactive tapering courses of steroids, and all patients remain clinically stable.

A fourth cohort is enrolling three patients at the 1.0 × 10^13 GC/kg dose, using prophylactic steroids.

Patients will receive an 8-week tapering regimen of prophylactic steroids, starting at least 5 days prior to dosing with DTX301 at a starting steroid dose of 60 mg/day.

The first patient is expected to be enrolled in the first half of 2020, and data from the prophylactic steroid cohort are expected in the second half of 2020.

We have also had discussions with the FDA regarding the potential Phase 3 study design.

Ammonia is expected to be a primary endpoint based on direct FDA feedback to date, with ureagenesis as a measure of biologic activity that supports the decision for patients to discontinue alternate pathway medications.

In May 2020, we announced updated positive data from the ongoing Phase 1/2 study at the ASGCT annual meeting.

The updated data confirmed that all three patients in the third dose cohort were responders to DTX301 as shown by sustained meaningful increases in the rate of ureagenesis or reductions in ammonia levels.

Six of nine patients across all three cohorts have now responded to the gene therapy, including three females and three males.

All three complete responders, those who have discontinued all ammonia scavengers and liberalized their diets, remain clinically and metabolically stable after longer-term follow-up, up to 130 weeks for the longest patient.

In January 2021, we announced positive longer-term safety and efficacy data from the first three cohorts.

The six responders identified at ASGCT in May 2020 continued to demonstrate durable metabolic control.

The three complete responders were stable through 104, 130, and 156 weeks post-treatment with good ammonia control despite discontinuation of their alternative pathway medications and protein-restricted diets.

The three other responders also remained stable through Weeks 52 and 130 and were either continuing to taper medications and diet or intended to continue tapering once COVID-19 restrictions are lifted and patients could be more closely followed in clinic.

As of January 2021, all responders remained in excellent clinical condition with no significant adverse events, hospitalizations, or other events related to OTC deficiency.

Two of three patients have been dosed in the prophylactic steroid cohort, the final cohort in the Phase 1/2 study, at the same dose as in Cohort 3.

Through up to 18 weeks post-dosing, both patients were doing well clinically with good metabolic control and there had been no treatment related serious adverse events.

We completed the initial Scientific Advice process with the EMA regarding the Phase 3 development plan and continue to have discussions with the FDA regarding the Phase 3 study of DTX301.

The EOP2 meeting with the FDA is scheduled to occur late in the first quarter of 2021, barring any unforeseen delays.

Based on regulatory feedback to date, the proposed Phase 3 study design is currently expected to include approximately 50 patients, randomized 1:1 to DTX301 dosed at 1.7 x 10^13 GC/kg, as calculated using a new ddPCR test method, or placebo and followed for 48 weeks initially.

The change in 24-hour ammonia levels is expected as the primary endpoint.

The entry criteria will allow patients with higher baseline ammonia levels than in the Phase 1/2 study to allow sufficient power to assess the change in ammonia.

The primary endpoint will be supported by the change in the rate of ureagenesis as a key secondary endpoint that evaluates

the capacity to generate urea from ammonia.

Additional secondary endpoints include reduction or discontinuation of scavenger medications and normalization of protein-restricted diet.

The Phase 3 study is expected to begin dosing in the second half of 2021.

Placebo patients participating in the study will receive DTX301 at the end of the initial 48-week follow-up period.

We will continue to follow patients in the ongoing Phase 1/2 study during the Phase 3 study in order to augment the overall long-term data package supporting the durability of DTX301.

Please see “—License and Collaboration Agreements—Clinical Product Candidates—REGENXBIO Inc.” for a description of our license agreement with REGENXBIO Inc.

DTX201 for the treatment of Hemophilia A

DTX201 (BAY 2599023) is a Factor VIII gene therapy program for the treatment of hemophilia A that is partnered with Bayer Healthcare LLC, or Bayer, utilizing our proprietary HeLa platform.

Hemophilia A is the most common form of hemophilia with approximately 144,000 patients in the developed world.

Data from the first dose cohort (n=2, dose of 5.0 x 10^12 GC/kg) of the Phase 1/2 study of DTX201 in hemophilia A was presented at the American Society of Hematology Annual Meeting in December 2019, and longer-term data from the first dose cohort and new data from the second dose cohort (n=2, dose of 1.0 x 10^13 GC/kg), was presented at the European Association for Haemophilia and Allied Disorders conference in February 2020.

One patient in Cohort 1 and both patients in Cohort 2 demonstrated clinically meaningful improvements in FVIII levels.

The patient in Cohort 1 experienced four bleeds post-treatment compared to 99 bleeds the prior year.

Both patients in dose cohort 2 achieved clinically meaningful FVIII levels out to 24 and 30 weeks.

Patient 4 in Cohort 2 has been bleed-free and treatment-free for up to seven months, as of the data cutoff.

Patient 4 had mild ALT/AST elevations that were managed with a short tapering course of corticosteroids.

Dose escalation in the Phase 1/2 study is ongoing.

Please see “—License and Collaboration Agreements—Clinical Product Candidates—Bayer” for a description of our license agreement with Bayer.

GTX-102 for the treatment of Angelman Syndrome

GTX-102, is an antisense oligonucleotide, or ASO, that is being developed for the treatment of Angelman syndrome, a debilitating and rare neurogenetic disorder, in collaboration with GeneTx Biotherapeutics LLC, or GeneTx.

In September 2019, we announced that the FDA granted Orphan Drug Designation and Rare Pediatric Disease Designation to GTX-102 for the treatment of Angelman syndrome.

In January 2020, we announced that GeneTx’s IND Application for GTX-102 was filed with the FDA and is now active.

Enrollment in the Phase 1/2 study is expected to begin in the first half of 2020.

UX143 (setrusumab) for the treatment of Osteogenesis Imperfecta (OI), in collaboration with Mereo BioPharma 3 Limited, or Mereo

UX143 is a fully human monoclonal antibody that inhibits sclerostin, a protein that acts on a key bone-signaling pathway and inhibits the activity of bone-forming cells.

By blocking inhibitory effects of sclerostin, the anti-sclerostin antibody causes new bone formation, increased production of collagen, and increased bone mineral density and strength.

Sclerostin inhibition also reduces excessive bone resorption, further enhancing the impact on bone density.

Setrusumab has received orphan drug designation from the FDA and EMA, rare pediatric disease designation from the FDA, and was accepted into the EMA’s Priority Medicines program (PRIME).

OI is a rare genetic disorder that is characterized by fragile bones and reduced bone mass resulting in bones that break easily, loose joints, and weakened teeth.

In severe cases, those with OI may experience hundreds of fractures in a lifetime.

In addition, people with OI often suffer muscle weakness, early hearing loss, fatigue, curved bones, scoliosis, respiratory problems, and short stature, leading to significant effects on overall health and quality of life.

The majority of cases of OI (estimated at approximately 90%) are caused by a dominant mutation in a gene coding for type I collagen, a key component of healthy bone.

Current treatment of OI is supportive, focusing on minimizing fractures and maximizing mobility, but to date, there are no FDA or EU approved treatments.

There are an estimated 60,000 patients in the developed world affected by OI.

On January 25, 2021, after the early termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 and satisfaction of other customary closing conditions under our collaboration and license agreement with Mereo, we closed the transactions under the agreement and pursuant to the terms thereof, we made a payment of $50 million to Mereo.

We expect to start a pediatric Phase 2/3 study in the second half of 2021.

Development plans are being finalized which may include changes to current study designs, and will require discussions with regulatory agencies.

The objective of a pediatric Phase 2/3 study would first focus on determining the optimal dose based on increases in collagen production using serum P1NP levels and an acceptable safety profile.

Following determination of the dose, we currently intend to adapt the study into a pivotal Phase 3 stage, evaluating fracture reduction over an estimated 15 to 24 months as the primary endpoint, subject to regulatory review.

A separate pivotal study is also currently being planned for adults with OI.

Please see “—License and Collaboration Agreements—Clinical Product Candidates—Mereo” for a description of our license and collaboration agreement with Mereo.

GTX-102 for the treatment of Angelman Syndrome, partnered with GeneTx

GTX-102 is an antisense oligonucleotide, or ASO, that is being developed for the treatment of Angelman syndrome, a debilitating and rare neurogenetic disorder caused by loss-of-function of the maternally inherited allele of the UBE3A gene.

There are an estimated 60,000 patients in the developed world affected by Angelman syndrome.

GTX-102 was granted Fast Track designation, Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA.

GTX-102 is being developed in collaboration with GeneTx Biotherapeutics LLC (GeneTx).

In March 2020, we, along with our partner GeneTx, announced the initiation of a Phase 1/2 open-label, multiple-dose, dose-escalating study (GTX-102-001) to evaluate the safety, tolerability, and potential efficacy of GTX-102 in pediatric patients with Angelman syndrome.

Five patients have received GTX-102 treatment to date and signs of clinical improvement in multiple domains of Angelman syndrome were reported early in dosing, After the fifth patient was dosed, the patient experienced a serious adverse event (SAE) of lower extremity weakness and the companies paused enrollment and dosing in the study.

Subsequently, similar SAEs of lower extremity weakness were reported in the other four patients following treatment at the highest doses.

The SAEs were assessed as mild or moderate in severity, improved over a period of a few weeks and all have fully resolved.

Full safety information has been submitted to the FDA.

A formal clinical hold was issued by the FDA on study GTX-102-001 during the fourth quarter of 2020.

In the fourth quarter of 2020, along with our partner GeneTx, we announced positive interim preliminary data from study GTX-102-001 which indicated substantial improvements in all patients in at least two disease domains including communication, behavior, sleep, gross motor function, and fine motor function as measured by the CGI-I-AS for Patients 1 through 4 at day 128, and Patient 5 at Day 86.

These improvements were also supported by other scores, including the Bayley Scales of Infant and Toddler Development (Bayley-4), where multiple patients improved on receptive or expressive communication sub-scales.

Also in the Observed Reported Communication Ability (ORCA) measure of expressive, receptive, and pragmatic communication, three patients, ages 5, 10, and 15, demonstrated clinically relevant increases at day 128 and two patients did not have notable changes.

In December 2020, a substantial information amendment was submitted to the FDA including follow-up safety information for the five patients dosed and toxicology data in nonhuman primates that demonstrate d no evidence of the safety issue described above at higher repeat dosing.

The amendment also included a safety evaluation of the SAEs , which supported that causality of the SAEs could be due to local contact toxicity.

An amended dosing and administration plan has been proposed to the FDA.

The changes reflected in the amended plan are designed to reduce the local contact time and concentration of the drug;

the amended dosing plan is within the dosing range for which clinical activity was observed but below doses associated with the SAEs.

As of January 2021 the study remains on clinical hold, but is currently expected to resume enrollment and dosing in the first half of 2021, assuming resolution of FDA requests and approval to proceed.

Once the study has resumed, we currently expect a dditional interim data from the study in the second half of 2021.

A Clinical Trial Application (CTA) was accepted in Canada in March 2020 and a protocol and a revised protocol incorporating the new dosing and administration plan will be submitted.

The companies are also in the process of expanding the study to other countries using the amended dosing and administration plan.

Please see “—License and Collaboration Agreements—Clinical Product Candidates—GeneTx” for a description of our collaboration agreement with GeneTx.

Preclinical Pipeline

UX701 for the treatment of Wilson Disease

UX701 is in preclinical development for Wilson disease, a rare inherited disorder caused by mutations in the ATP7B gene, which results in deficient production of ATP7B, a protein that transports copper.

UX701 is an investigational AAV type 9 gene therapy designed to deliver stable expression of a truncated version of the ATP7B copper transporter following a single intravenous infusion.

It has been shown in preclinical studies to improve copper distribution and excretion from the body and reverse pathological findings of Wilson liver disease.

UX701 was granted Orphan Drug Designation in the United States and EU.

Wilson disease is a rare inherited disorder caused by mutations in the ATP7B gene, which results in deficient production of ATP7B, a protein that transports copper.

Loss of function of this copper-binding protein results in the accumulation of copper in the liver and other tissues, most notably the central nervous system.

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Wilson disease affects more than 50,000 individuals in the developed world.

An IND for UX701 is expected by the end of 2020.

In January 2021, we announced that the FDA has cleared the IND application for UX701.

We currently expect enrollment in a seamless single-protocol Phase 1/2/3 study to begin in the first half of 2021.

In February 2021, UX701 received Fast Track Designation from the FDA.

This allows for early and frequent communication throughout the entire drug development and review process and reflects the serious, unmet need for patients with Wilson disease.

UX053 for the treatment of glycogen storage disease type III, or GSDIII

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GSDIII can cause hepatomegaly, hypoglycemia, hyperlipidemia, some progressive liver cirrhosis, and muscle disease later in life, and affects more than 10,000 patients in the developed world.

We currently expect UX053 to be our first mRNA program in the clinic, with an IND planned for the first half of 2021 and initiation of the trial in the second half of 2021.

Please see “—License and Collaboration Agreements—Preclinical Pipeline—Arcturus” for a description of our collaboration agreement with Arcturus.

UX068 for the treatment of creatine transporter deficiency, or CTD

UX068 is in preclinical development for the treatment of CTD, an X-linked recessive disorder due to mutations in the SLC6A8 gene.

Patients with CTD can suffer from CNS deficits, seizures, progressive intellectual disability, autism, speech/language/gross motor delays, and muscle hypotonia and hypotrophy.

CTD affects an estimated 30,000 to 50,000 patients in the developed world.

Other preclinical programs

We continue to work on other compounds in various preclinical stages of development.

In the case of indications that we are targeting, it is possible that other companies may produce, develop, and commercialize compounds that might treat these diseases.

With respect to Crysvita, although we are not aware of any other products currently in clinical development for the treatment of XLH, it is possible that competitors may produce, develop, and commercialize therapeutics, or utilize other approaches such as gene therapy, to treat XLH.

With respect to Crysvita, although we are not aware of any other products currently in clinical development for the treatment of XLH and TIO, it is possible that competitors may produce, develop, and commercialize therapeutics, or utilize other approaches such as gene therapy, to treat XLH and TIO.

Most pediatric patients with XLH are managed using oral phosphate replacement and/or vitamin D therapy, which is relatively inexpensive and therefore may adversely affect our ability to commercialize Crysvita, if approved, in some countries.

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Typically, enzyme replacement therapy has had an impact on bone and connective tissue disease in other disorders when patients were treated early.

With respect to UX007/triheptanoin, there are currently no approved drugs or treatments for patients with LC-FAOD.

LC-FAOD is commonly treated with diet therapy and MCT oil.

UX007 may compete with this approach.

Although we believe that UX007 should be considered a drug and will be regulated that way, it is possible that other companies or individuals may attempt to produce triheptanoin for use in LC-FAOD.

With respect to Dojolvi , although we are not aware of any other compounds currently in clinical development for LC-FAOD , LC-FAOD is commonly treated with diet therapy and MCT oil .

Dojolvi may compete with this approach .

Although we believe that Dojolvi should be considered a drug and will be regulated that way, it is possible that other companies or individuals may attempt to produce triheptanoin for use in LC-FAOD.

Investigators are testing triheptanoin in clinical studies across multiple indications, including LC-FAOD.

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In addition, Reneo Pharmaceuticals is developing REN001, a PPAR delta agonist, in Phase 1b for LC-FAOD and other genetic myopathies.

With respect to DTX401, there are currently no pharmacologic treatments for patients with GSDIa and we are not aware of any programs in clinical development .

With respect to DTX301, the current treatments for patients with OTC deficiency are nitrogen scavenging drugs and severe limitations in dietary protein.

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Liver transplant may also be a solution for OTC deficiency.

In addition, Kaleido Biosciences is developing KB195, a synthetic glycan, in Phase 2 for urea cycle disorders, including OTC deficiency.

With respect to DTX401, there are currently no pharmacologic treatments for patients with GSDIa and we are not aware of any programs in clinical development .

In addition, Kaleido Biosciences is developing KB195, a synthetic glycan, in Phase 2 for urea cycle disorders, including OTC deficiency, and Arcturus Therapeutics is developing ARCT-810, a messenger RNA therapy, in Phase 1b for OTC deficiency.

With respect to GTX-102, there are currently no approved drugs for Angelman syndrome.

Many patients take general treatments to try to manage specific symptoms, such as seizures or sleep disturbances, but there are no treatments available that address the underlying biology of the disease.

We are aware of other ASOs in preclinical development for Angelman syndrome, as well as gene therapy programs.

In addition, Ovid Therapeutics is developing OV101, a GABA A receptor agonist, in Phase 3 for Angelman syndrome.

We are aware of other ASOs in preclinical and clinical development for Angelman syndrome, including a program from Roche in a Phase 1 study, as well as preclinical gene therapy programs.

In addition, Neuren is developing NNZ-2591, an IGF-1 analog, in Phase 1 for Angelman syndrome.

With respect to UX701, there are no currently approved treatments that address the underlying cause of Wilson disease.

Many patients are on chelator therapies, but these fail to address the mutated ATP7B copper transporter gene.

We are aware of another gene therapy, VTX-801, that is in development by Vivet Therapeutics, in collaboration with Pfizer, for Wilson disease.

License and Collaboration Agreements

Our products and current product candidate pipeline have been either in-licensed from academic institutions or derived from partnerships with other pharmaceutical companies.

Our products and some of our current product candidates have been either in-licensed from academic institutions or derived from partnerships with other pharmaceutical companies.

Following is a description of our significant license and collaboration agreements.

Approved Product s

Approved Products

Kyowa Kirin Co., Ltd.

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As described below, we and KKC share commercial responsibilities and profits in the profit-share territory until April 2023, KKC has the commercial responsibility in the European territory, and we are responsible for commercializing burosumab in Latin America.

In the profit-share territory, KKC books sales of products and we have the sole right to promote the products for a specified period of time, with KKC increasingly participating in the promotion of the products until April 2023, which is five years from commercial launch, after which KKC will have the right to promote the products, subject to a limited promotion right retained by us.

In the profit-share territory, KKC books sales of products and we have the sole right to promote the products for a specified period of time, with KKC having the right to increasingly participat e in the promotion of the products until the transition date of April 2023, which is five years from commercial launch .

A fter April 2023, KKC will have the right to promote the products, subject to a limited pro motion right retained by us.

See “Item I.A.

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KKC also supplies all quantities of product for commercial sales in the profit-share territory and in Latin America.

The supply price in the profit-share territory and Latin America is 35% of net sales price through December 31, 2022 and 30% thereafter.

The supply price in the profit-share territory and Latin America is 35% of the net sales price through December 31, 2022 and 30% thereafter.

The remaining profit or loss from commercializing products in the profit-share territory is shared between us and KKC on a 50/50 basis until April 2023.

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Under the terms of the license agreement, SLU granted us an exclusive worldwide license to make, have made, use, import, offer for sale, and sell therapeutics related to SLU’s beta-glucuronidase product for use in the treatment of human diseases.

Under this agreement, we agreed to use best efforts to develop and commercialize a licensed product as soon as practicable consistent with sound and reasonable business practices and judgment.

Under the license agreement, upon reaching a certain level of worldwide sales of the product, we will pay to SLU a low single-digit royalty on net sales of the licensed products in any country or region, subject to certain potential deductions.

Our obligation to pay royalties to SLU continues on a country-by-country basis until the expiration of the last-to-expire licensed patent covering the product in such country or, in the United States, Japan, and Europe, until the later expiration of any orphan drug exclusivity.

We may terminate the agreement for convenience at any time and SLU may terminate the agreement for our material breach, bankruptcy, or challenge of the licensed patents or technology, and SLU may terminate the agreement or render our license non-exclusive if we fail to meet our diligence obligations.

Unless terminated as set forth above, this license agreement continues in full force and effect until the latest of expiration of the last patent based on technology licensed under the agreement, at which point our license becomes fully paid.

Clinical Product Candidates

Under the license agreement, we are obligated to pay to SLU a low single-digit royalty on net sales of the licensed products in the United States, Europe, or Japan, subject to certain potential deductions.

Our obligation to pay royalties to SLU in these territories continues until the expiration of any orphan drug exclusivity.

We may terminate the agreement for convenience at any time and SLU may terminate the agreement for our material breach, bankruptcy, or challenge of the licensed technology, and SLU may terminate the agreement or render our license non-exclusive if we fail to meet our diligence obligations.

Unless terminated as set forth above, this license agreement continues in full force and effect until the latest expiration of any orphan drug exclusivity in the United States, Europe, or Japan, at which point our license becomes fully paid.

Baylor Research Institute

In September 2012, we entered into a license agreement with Baylor Research Institute, or BRI, under which we exclusively licensed certain intellectual property related to triheptanoin.

The license includes patents, patent applications, know-how, and intellectual property related to the composition and formulation of triheptanoin as well as its use in treating a number of orphan diseases, including LC-FAOD.

In September 2012, we entered into a license agreement with Baylor Research Institute, or BRI, under which we exclusively licensed certain intellectual property related to Dojolvi.

The license includes patents, patent applications, know-how, and intellectual property related to the composition and formulation of Dojolvi as well as its use in treating a number of orphan diseases, including LC-FAOD.

The license grant includes the sole right to develop, manufacture, and commercialize licensed products for all human and animal uses.

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Unless terminated by its terms, this license agreement continues in full force and effect, on a product-by-product and country-by-country basis, until our royalty obligations expire, at which point our license from BRI with respect to such product in such country becomes irrevocable, perpetual, fully paid and royalty-free.

Clinical Product Candidates

REGENXBIO Inc.

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If the 2013 license agreement is terminated with respect to an indication, we grant certain rights to REGENX, including transferring ownership of any applicable regulatory approvals and granting an exclusive license under certain of our intellectual property for use with respect to products covered by the intellectual property we had licensed from REGENX in that indication.

In March 2015, we entered into an option and license agreement with REGENX under which we were granted an option to deve lop product candidates to treat Wilson disease and another disease indication.

We have exercised our options available to develop a product candidate under this agreement.

The 2015 option and license agreement grants us an exclusive worldwide license to make, have made, use, import, sell, and offer for sale licensed products with respect to such disease indication s, subject to certain exclusions .

In March 2015, we entered into an option and license agreement with REGENX pursuant to which we have an exclusive worldwide license to make, have made, use, import, sell, and offer for sale licensed products to treat Wilson disease and CDKL5 deficiency.

We do not have the right to control prosecution of the in-licensed patent applications, and our rights to enforce the in-licensed patents are subject to certain limitations.

Under the 2015 option and license agreement, we pay or will pay REGENX an annual maintenance fee and certain milestone fees per disease indication, mid to high single-digit royalty percentages on net sales of licensed products, and mid-single to low double-digit percentages of any sublicense fees we receive from sublicense s for the license d intellectual property rights.

We are required to develop licensed products in accordance with certain milestones.

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If the 2015 option and license agreement is terminated with respect to an indication, we grant certain rights to REGENX, including transferring ownership of any applicable regulatory approvals and granting an exclusive license under certain of our intellectual property for use with respect to products covered by the intellectual property we had licensed from REGENX in that indication.

In March 2020, we entered into a license agreement with REGENX, for an exclusive, sublicensable, worldwide license to REGENX’s NAV AAV8 and AAV9 vectors for the development and commercialization of gene therapy treatments for a rare metabolic disorder.

In return for these rights, we made an upfront payment and pay or will pay certain annual fees, milestone payments and royalties on any net sales of products incorporating the licensed intellectual property that range from a high single-digit to low double-digit .

In June 2014 , we entered into an agreement with Bayer to research, develop and commercialize AAV gene therapy products for treatment of hemophilia A, which was amended and restated in June 2019.

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In the event of termination, we shall pay University of Pennsylvania the amount needed to cover costs through the effective termination date as well as allowable commitments extending beyond the termination date (up to one-fourth of the total budget).

In May 2016, we entered into a research, collaboration and license agreement with the University of Pennsylvania under which we are collaborating on the pre-clinical development of gene therapy products for the treatment of citrullinemia type I, phenylketonuria, and Wilson disease, each, a Subfield.

In May 2016, we entered into a research, collaboration and license agreement with the University of Pennsylvania under which we are collaborating on the pre-clinical development of gene therapy products for the treatment of phenylketonuria and Wilson disease, each, a Subfield.

Under the agreement, we were granted an exclusive, worldwide, royalty-bearing right and license to certain patent rights arising out of the research program, and a non-exclusive, worldwide, royalty-bearing right and license to certain University of Pennsylvania intellectual property, in each case to research, develop, make, have made, use, sell, offer for sale, commercialize and import licensed products in each Subfield for the term of the agreement.

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We will also make milestone payments of up to $25.0 million per approved product if certain commercial milestones are achieved.

In August 2019, we announced an agreement with GeneTx to collaborate on the development of GeneTx’s GTX-102.

In August 2019, we entered into an agreement with GeneTx to collaborate on the development of GeneTx’s GTX-102.

Under the terms of the agreement, we made an upfront payment of $20.0 million which included an exclusive option to acquire GeneTx.

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If we exercise the purchase option, we will pay a purchase price to acquire GeneTx, payments upon achieving regulatory and commercial milestones, and royalties on any product sales.

In December 2020, we entered into a License and Collaboration Agreement with Mereo to collaborate on the development of setrusumab.

Under the terms of the agreement, we will lead future global development of setrusumab in both pediatric and adult patients with OI and were granted an exclusive license to develop and commercialize setrusumab in the U.S., Turkey, and the rest of the world, excluding the European Economic Area, United Kingdom, and Switzerland, or the Mereo Territory, where Mereo retains commercial rights.

Each party will be responsible for post-marketing commitments and commercial supply in their respective territories.

Upon the closing of the transactions under the License and Collaboration Agreement with Mereo in January 2021, we made a payment of $50.0 million to Mereo and will be required to make payments of up to $254.0 million upon the achievement of certain clinical, regulatory, and commercial milestones.

We will pay for all global development costs as well as tiered double-digit percentage royalties to Mereo on net sales in the U.S., Turkey, and the rest of the world, and Mereo will pay us a fixed double-digit percentage royalty on net sales in the Mereo Territory.

Preclinical Pipeline

We signed a research collaboration and license agreement with Arcturus to develop mRNA therapeutics for select rare disease targets in October 2015.

In October 2015, we entered into a Research Collaboration and License Agreement with Arcturus Therapeutics Holdings Inc., or Arcturus, to develop mRNA therapeutics for select rare disease targets.

The Arcturus collaboration may help us address a wider range of rare diseases than possible with current approaches.

As part of the collaboration, Arcturus will utilize its UNA Oligomer™ chemistry and LUNAR™ nanoparticle delivery platform to initially design and optimize mRNA therapeutics for two targets selected by us;

we also have the option to add up to eight additional targets during the collaborative research period.

In June 2019, we announced the expansion of our research and collaboration arrangement with Arcturus Therapeutics Holdings Inc., or Arcturus, to discover and develop mRNA, DNA and siRNA therapeutics for up to 12 rare disease targets pursuant to the terms of an amendment to the Research Collaboration and License Agreement, or License Agreement, and Equity Purchase Agreement.

As part of the collaboration, we may use Arcturus’ LUNAR® nanoparticle delivery platform to develop mRNA therapeutics for the treatment of various rare disease targets, subject to certain exclusions and restrictions.

In June 2019, we announced the expansion of our research and collaboration arrangement with Arcturus, to discover and develop mRNA, DNA and siRNA therapeutics for up to 12 rare disease targets pursuant to the terms of an amendment to the 2015 R esearch C ollaboration and L icense A greement, or 2015 license agreement, and equity purchase agreement.

In connection with the amendment to the 2015 license agreement, we made a $6.0 million cash upfront payment to Arcturus and also purchased 2,400,000 shares of Arcturus’ common stock at a stated value of $10.00 per share.

We have an option to purchase an additional 600,000 shares of Arcturus’ common stock at $16.00 per share.

In May 2020, w e exercised an option to purchase an additional 600,000 shares of Arcturus’ common stock at $16.00 per share .

In December 2020, we sold 800,000 shares at a weighted - average price of $100.81 .

As of December 31, 2020, we held 2,200,000 shares of Arcturus common stock.

Arcturus is entitled to preclinical, clinical, regulatory, and sales milestone payments for each product developed under the collaboration.

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Arcturus is also entitled to reimbursement of related research expenses and royalties on commercial sales.

Solid Biosciences Inc.

In October 2020, we entered into a strategic Collaboration and License Agreement with Solid Biosciences Inc., or Solid, and received an exclusive license for any pharmaceutical product that expresses Solid’s proprietary microdystrophin construct from AAV8 and variants thereof in clade E for use in the treatment of Duchenne muscular dystrophy and other diseases resulting from lack of functional dystrophin, including Becker muscular dystrophy.

We will collaborate to develop products that combine Solid’s differentiated microdystrophin construct, our HeLa producer cell line (PCL) manufacturing platform, and our AAV8 variants.

Solid will also provide development support and was granted an exclusive option to co-invest in products we develop for profit share participation in certain territories.

Pursuant to the terms of the Stock Purchase Agreement with Solid that was entered into in October 2020 in connection with the collaboration, we also purchased 7,825,797 shares of Solid’s common stock for an aggregate price of $40.0 million.

In March 2020, we entered into a License and Technology Access Agreement, or the License Agreement with Daiichi Sankyo Co., Ltd., or Daiichi Sankyo, pursuant to which, we granted Daiichi Sankyo a non-exclusive license to intellectual property, including know-how and patent applications, with respect to our HeLa PCL and HEK293 transient transfection manufacturing technology platforms for AAV-based gene therapy products.

We retained the exclusive right to use the manufacturing technology for our current target indications and additional indications identified now and in the future.

We are providing certain technical assistance and technology transfer services during the technology transfer period of three years to enable Daiichi Sankyo to use the technologies for its internal gene therapy programs.

Daiichi Sankyo has an option to extend the technology transfer period including know-how improvements by two additional one-year periods by paying a fixed amount for each additional year.

Daiichi Sankyo will be responsible for the manufacturing, development, and commercialization of their products manufactured with the licensed technology;

however, we have the option to co-develop and co-commercialize rare disease products at the IND stage.

We may also provide strategic consultation to Daiichi Sankyo on the development of both AAV-based gene therapy products and other products for rare diseases.

Under the terms of the License Agreement, Daiichi Sankyo made an upfront payment of $125.0 million and is obligated to pay an additional $25.0 million milestone upon the successful completion of the technology transfer of the HeLa PCL and HEK293 platforms, as well as single-digit royalties on net sales of products manufactured in either system.

Daiichi Sankyo is reimbursing us for all costs associated with the transfer of the manufacturing technology.

We also entered into a Stock Purchase Agreement, or SPA, with Daiichi Sankyo, pursuant to which Daiichi Sankyo purchased 1,243,913 shares of our common stock in exchange for $75.0 million in cash during the first quarter of 2020.

Daiichi Sankyo is subject to a three-year standstill and restrictions on sale of the shares (subject to customary exceptions or release).

In June 2020, we executed a subsequent license agreement, or the Sublicense Agreement, with Daiichi Sankyo for transfer of certain technology in consideration for a payment of $8.0 million and annual maintenance fees, milestone payments, and royalties on any net sales of products incorporating the licensed intellectual property.

Patents and Proprietary Rights

The proprietary nature of, and protection for, our products, product candidates, processes, and know-how are important to our business.

Our success depends in part on our ability to protect the proprietary nature of our products, product candidates, technology, and know-how, to operate without infringing on the proprietary rights of others, and to prevent others from infringing our proprietary rights.

We seek patent protection in the United States and internationally for our products, product candidates, and other technology.

Our policy is to patent or in-license the technology, inventions and improvements that we consider important to the development of our business.

In addition to patent protection, we use other means to protect our proprietary rights, including the pursuit of marketing or data exclusivity periods, orphan drug status, and similar rights that are available under regulatory provisions in certain countries, including the United States, Europe, Japan, and China.

Our success depends in part on our ability to protect our products, product candidates, processes, and know-how, to operate without infringing on the proprietary rights of others, and to prevent others from infringing our proprietary rights.

We seek patent protection in the United States and internationally for our products, product candidates, and processes.

Our policy is to patent or in-license the technologies, inventions and improvements that we consider important to the development of our business.

In addition to patent protection, we rely on trade secrets, know-how, and continuing innovation to develop and maintain our competitive position.

We also use other means to protect our products and product candidates , including the pursuit of marketing or data exclusivity periods, orphan drug status, and similar rights that are available under regulatory provisions in certain countries, including the United States, Europe, Japan, and China.

See “Government Regulation—U.S.

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Government Regulation — Pediatric Studies and Exclusivity,” “Government Regulation—U.S.

Government Regulation — Patent Term Restoration,” “Government Regulation—U.S.

Government Regulation — Biosimilars and Exclusivity,” “Government Regulation—U.S.

Government Regulation — Abbreviated New Drug Applications for Generic Drugs and New Chemical Entity Exclusivity,” and “Government Regulation—EU Regulation — Orphan Designation and Exclusivity” below for additional information.

We also rely on trade secrets, know-how, and continuing innovation to develop and maintain our competitive position.

We cannot be certain that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our existing patents or any patents granted to us in the future will be commercially useful in protecting our technology.

We seek regulatory approval for our product candidates in disease areas with high unmet medical need, significant market potential, and where we expect to have a proprietary position through patents covering various aspects of our product candidates, such as composition, dosage, formulation, use, and manufacturing process, among others.

Government Regulation — Abbreviated New Drug Applications for Generic Drugs and New Chemical Entity Exclusivity,” “Government Regulation—U.S.

Government Regulation — Patent Term Restoration,” “Government Regulation—EU Regulation — Orphan Designation and Exclusivity , ” and “Government Regulation —EU Regulation — New Chemical Entity Exclusivity” below for additional information.

We seek regulatory approval for our products and product candidates in disease areas with high unmet medical need, significant market potential, and where we expect to have a proprietary position through patents covering various aspects of our product candidates, such as composition, dosage, formulation, use, and manufacturing process, among others.

Our success depends in part on an intellectual property portfolio that supports our future revenue streams and erects barriers to our competitors.

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Despite these measures, any of our intellectual property and proprietary rights could be challenged, invalidated, circumvented, infringed or misappropriated, or such intellectual property and proprietary rights may not be sufficient to achieve or maintain market exclusivity or otherwise to provide competitive advantages.

For more information, please see “Risks Related to Our Intellectual Property.”

We own or in-license a number of patents in the U.S.

and foreign countries that cover our products, product candidates, and methods of their use.

We also cannot be certain that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our existing patents or any patents granted to us in the future will be commercially useful in protecting our products, product candidates, or processes.

For more information, please see “Item I.A.

Risk Factors Risks Related to Our Intellectual Property.”

As of December 31, 2020, we own, jointly own, or have exclusive rights to more than 140 issued and in-force patents (not including individually validated national patents in European Patent Convention member countries) that cover one or more of our products or product candidates, methods of their use, or methods of their manufacture, including more than 45 in-force patents issued by the U.S.

Patent and Trademark Office (the USPTO).

Furthermore, as of December 31, 2020, we own, jointly own, or have exclusive rights to more than 250 pending patent applications, including more than 50 pending U.S.

applications.

With respect to our owned or in-licensed issued patents in the U.S.

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The exact duration of the extension depends on the time we spend in clinical studies as well as getting marketing approval from the FDA.

The exclusivity positions for our commercial products, Mepsevii and Crysvita, and our clinical-stage product candidates as of December 31, 2019 are summarized below.

The exclusivity positions as of December 31, 2020 for our commercial products and our clinical-stage product candidates are summarized below.

Crysvita (Burosumab) Exclusivity

We have in-licensed rights from KKC to patents and patent applications relating to Crysvita and its use for the treatment of XLH and various other hypophosphatemic conditions.

Pursuant to this license, we have rights to a number of issued patents and pending applications, including five issued U.S.

patents, as well as patents and applications in other jurisdictions covering generic and specific antibodies against FGF23 as well as their use for the treatment of XLH and related conditions.

We have in-licensed rights from KKC to patents and patent applications relating to Crysvita and its use for the treatment of XLH, TIO, and various other hypophosphatemic conditions.

Pursuant to this license, we have rights to a number of issued patents and pending applications, including six issued U.S.

patents, as well as patents and applications in other jurisdictions covering generic and specific antibodies against FGF23 as well as their use for the treatment of XLH, TIO, and related conditions.

The patent terms for the issued patents in the U.S.

are from 2022 to 2029 (without extension of patent term), while the issued patents outside the U.S.

expire between 2021 and 2028 (without extension of patent term).

KKC has applied for an extension of patent term in the U.S.

and Europe for Crysvita to 2032 and 2033, respectively.

We also jointly own with KKC a pending application in the U.S.

and corresponding foreign patent applications relating to dosing regimens for administration of anti-FGF23 antibodies, including Crysvita.

Any patents issuing from these jointly-owned applications would be expected to expire in 2035.

are from 2022 to 2035, while the issued patents outside the U.S.

expire between 2021 and 2035.

For patents covering the Crysvita composition of matter, KKC has applied to extend the patent term in the U.S.

from 2029 to 2032 and in Europe from 2028 to 2033.

In addition to the foregoing patent protections, Crysvita is protected in the U.S.

by regulatory data exclusivity until 2030 and by orphan drug exclusivity for treating XLH until 2025.

by regulatory exclusivity until 2030 and by orphan drug exclusivity for treating XLH and TIO until 2025 and 2027, respectively.

Mepsevii (Vestronidase Alfa) Exclusivity

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Mepsevii is also protected in the U.S.

by regulatory data exclusivity until 2029 and by orphan drug exclusivity for treating MPS VII until 2024.

Outside the U.S., we own issued patents expiring in 2035 in Australia, China, Colombia, Europe, Japan, Mexico, Russia, and Singapore, as well as pending patent applications in other territories, which cover Mepsevii and its use in the treatment of MPS VII.

UX007 Exclusivity

We have an exclusive license from the Baylor Research Institute, or BRI, to patents and patent applications relating to the UX007 composition and its use for the treatment of FAOD.

In the U.S., the in-licensed BRI patent portfolio includes issued patents with claims covering the UX007 composition that expire between 2020 and 2025 (without extension of patent term).

The BRI portfolio additionally includes issued U.S.

and foreign patents with claims covering the use of UX007 for the treatment of FAOD that expire in 2020 (without extension of patent term).

We also own a pending U.S.

patent application and corresponding foreign patent applications relating to our pharmaceutical-grade UX007 composition.

Any patents issuing from these owned applications would be expected to expire in 2034.

by regulatory exclusivity until 2029 and by orphan drug exclusivity for treating MPS VII until 2024.

Outside the U.S., we own issued patents expiring in 2035 in Australia, Canada, China, Colombia, Europe, Japan, Korea, Mexico, Russia, Singapore, and Taiwan, as well as pending patent applications in other territories, which cover Mepsevii and its use in the treatment of MPS VII.

Dojolvi (Triheptanoin) Exclusivity

We have an exclusive license from the BRI to patents and patent applications relating to Dojolvi and its use for the treatment of FAOD.

The in-licensed BRI patent portfolio includes issued patents in the U.S and Mexico that expire in 2025 and cover Dojolvi, as well as an issued patent in Canada that expires in 2025 and covers the use of Dojolvi for the treatment of FAOD.

In the U.S., we have applied to extend the term of a BRI patent covering Dojolvi from 2025 to 2029.

Beyond the aforementioned BRI patents and patent applications, we own a pending U.S.

patent application, corresponding foreign patent applications, and issued patents in Australia, Malaysia, and Taiwan relating to our pharmaceutical-grade Dojolvi composition;

these owned patents and any additional patents issuing from these owned applications are expected to expire in 2034.

Dojolvi is also protected in the U.S.

by regulatory exclusivity until 2025 and orphan drug exclusivity for treating FAOD until 2027.

DTX401 Exclusivity

We have two in-licenses to patents and patent applications covering elements of our DTX401 product candidate.

First, we have in-licensed patents owned by University of Pennsylvania (UPENN) and sublicensed to us by REGENX relating to the AAV8 capsid used in DTX401 that expire between 2022 and 2024 in the U.S., and in 2022 in foreign countries.

Second, we have a non-exclusive license from the National Institutes of Health (NIH) to an issued U.S.

patent expiring in 2034 (without extension of patent term) and corresponding foreign patents and patent applications covering a recombinant nucleic acid construct used in DTX401 that includes a codon-optimized version of the G6Pase gene.

We intend to pursue marketing and orphan drug exclusivity periods that are available under regulatory provisions in certain countries.

UX007 has received orphan designation in the U.S.

for FAOD and in Europe for various subtypes of FAOD.

DTX401 for the treatment of GSD1a has received orphan drug designation in the U.S.

DTX301 Exclusivity

We have in-licensed patents and patent applications owned by the University of Pennsylvania, or UPENN, relating to various adeno-associated viruses and vectors utilizing the capsids of those viruses.

These patents and patent applications are licensed or sublicensed to REGENXBIO and sublicensed to us.

We have in-licensed patents and patent applications owned by UPENN relating to various adeno-associated viruses and vectors utilizing the capsids of those viruses.

These patents and patent applications are licensed or sublicensed to REGENX and sublicensed to us.

Our product candidate DTX301 utilizes an AAV 8 capsid and a codon-optimized version of the OTC gene.

The in-licensed patents relevant to the AAV8 capsid expire between 2022 and 2024 in the U.S., and in 2022 in foreign countries.

Our in-license also includes an issued U.S.

patent expiring in 2035 (without extension of patent term) and corresponding foreign patent applications covering the codon-optimized version of the OTC gene used in DTX301.

Our in-license also includes two issued U.S.

patents expiring in 2035 (without extension of patent term) and corresponding foreign patents and patent applications covering the codon-optimized version of the OTC gene used in DTX301.

We intend to pursue marketing and orphan drug exclusivity periods that are available under regulatory provisions in certain countries.

DTX301 for the treatment of OTC deficiency has received orphan drug designation in the U.S.

DTX401 Exclusivity

We have two in-licenses to patents and patent applications covering elements of our DTX401 product candidate.

First, we have in-licensed patents owned by UPENN and sublicensed to us by REGENXBIO relating to the AAV8 capsid used in DTX401 that expire between 2022 and 2024 in the U.S., and in 2022 in foreign countries.

Second, we have a non-exclusive license from the National Institutes of Health (NIH) to issued U.S.

and European patents expiring in 2034 (without extension of patent term) and corresponding patent applications in other territories covering a recombinant nucleic acid construct used in DTX401 that includes a codon-optimized version of the G6Pase gene.

We intend to pursue marketing and orphan drug exclusivity periods that are available under regulatory provisions in certain countries.

DTX401 for the treatment of GSD1a has received orphan drug designation in the U.S.

We have registered trademarks covering the Ultragenyx word mark in the U.S.

UX143 (Setrusumab) Exclusivity

We have in-licensed rights from Mereo to patents and patent applications relating to setrusumab and its use for the treatment of OI.

Pursuant to our license from Mereo, we have exclusive rights outside of Europe to a first Mereo patent family that includes three issued U.S.

patents and corresponding issued foreign patents that relate to the setrusumab antibody, nucleic acids encoding the setrusumab antibody, and setrusumab’s use as a medicament.

Patents emanating from the first patent family expire in 2028 (without extension of patent term).

We also have exclusive rights outside of Europe to two additional Mereo patent families relating to the use of anti-sclerostin antibodies including setrusumab for the treatment of OI.

We expect any patents emanating from these two latter patent families to expire in 2037 (without extension of patent term).

We own registered trademarks covering the Ultragenyx word mark in the U.S.

and multiple other jurisdictions.

In addition, we have a registered trademark in the U.S.

In addition, we own a registered trademark in the U.S.

covering a stylized design of our Ultragenyx Pharmaceutical logo.

We also have registered trademarks in the U.S.

and other territories relating to our Mepsevii brand name for vestronidase alfa.

We also own registered trademarks in the U.S.

and other territories relating to our Mepsevii and Dojolvi brand names for vestronidase alfa and triheptanoin, respectively.

We additionally have a license from KKC to registered trademarks covering the Crysvita brand name for burosumab in the U.S., Canada, Turkey, and various Latin American territories.

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We do not own or operate manufacturing facilities for the cGMP production of clinical or commercial quantities of our product candidates.

We do, however, have process and analytical development and QC lab capabilities focused on the gene therapy technologies.

The use of contracted manufacturing and reliance on collaboration partners is relatively cost-efficient and has minimized the need for our direct investment in manufacturing facilities and additional staff early in development.

We do, however, have process and analytical development and QC lab capabilities focused on the gene therapy and nucleic acid technologies.

The use of contracted manufacturing and reliance on collaboration partners has minimized the need for our direct investment in manufacturing facilities and additional staff early in development.

Although we rely on contract manufacturers, we have personnel with extensive manufacturing experience to oversee our contract manufacturers.

All of our third-party manufacturers are subject to periodic audits to confirm compliance with applicable regulations and must pass inspection before we can manufacture our drugs for commercial sales.

While our third-party manufacturers have met our current manufacturing requirements, we intend to build our own GMP gene therapy manufacturing plant to mitigate potential program timeline delays, control manufacturing costs and reduce manufacturing lead times.

The recent addition of GMP QC lab capabilities is an example of this strategy.

While our third-party manufacturers have met our current manufacturing requirements, we are building our own GMP gene therapy manufacturing plant to attempt to mitigate potential program timeline delays, control manufacturing costs and reduce manufacturing lead times.

For the other non-gene therapy modalities, we primarily use third-party manufacturers to meet our projected needs for commercial manufacturing.

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All other raw materials are commercially available.

We intend to transfer the fill and finish activities for the manufacture of Mepsevii to a new site as the Rentschler manufacturing site in Laupheim, Germany is being discontinued.

We are transferring the fill and finish activities for the manufacture of Mepsevii to a new site as the Rentschler manufacturing site in Laupheim, Germany is being discontinued.

In preparation of this activity, we intend to maintain sufficient inventory levels as we identify an alternative supplier and transfer the fill and finish activities for Mepsevii to such supplier.

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All other raw materials are commercially available.

Product Candidates

The pharmaceutical-grade drug substance for UX007 is manufactured by IOI Oleo GmbH, or IOI Oleo, in Germany under an exclusive worldwide supply agreement, subject to certain limitations, executed in 2012 with an initial term of three years.

The pharmaceutical-grade drug substance for Dojolvi is manufactured by IOI Oleo GmbH, or IOI Oleo, in Germany under an exclusive worldwide supply agreement, subject to certain limitations, executed in 2012 with an initial term of three years.

The agreement automatically renews for two-year periods at the end of each then current term unless either party notifies the other party of its intention not to renew in writing at least three calendar months before the expiration of the then current term.

Additionally, if a party materially breaches an obligation under the agreement and does not cure such breach within 60 days of receiving notice of the breach from the non-breaching party, the non-breaching party may terminate the agreement immediately upon written notice to the breaching party.

Multiple parties have manufactured the UX007 drug product for us, which is not considered a very specialized task.

The drug substance and drug product for DTX301, our AAV product candidate, are manufactured on a non-exclusive basis by a contract manufacturing organization, or CMO, pursuant to cGMP requirements.

DTX 301 is currently manufactured using HEK293 adherent mammalian cells.

Adherent and suspension HEK293 cells are straightforward to grow and transfect readily, and as a result, are widely used in the biotechnology industry to produce therapeutic proteins and viral vectors for gene therapy on a small scale.

Vectors produced using HEK293 cells have been, or are being, used safely in multiple clinical trials, including trials conducted in the United States and EU by other biopharmaceutical companies and aca demic government institutions.

A key advantage of the HEK293 cell manufacturing system is flexibility and the relative speed with which AAV vectors can be manufactured for early Phase 1/2 clinical trials, allowing the establishment of early indications of therapeutic benefit in patients.

As we advance and scale up our processes for Phase 3 clinical and commercial scale manufacturing, we intend to transition from the HEK293 cell manufacturing scale used for our DTX301 Phase 1/2 programs to a cell-based suspension bioreactor format.

Similar to DTX301, the drug substance and drug product for DTX401 are manufactured on a non-exclusive basis by a CMO pursuant to cGMP requirements.

The drug product for Dojolvi is manufactured by Aenova Haupt Pharma Wolfratshausen GmbH, or Haupt Pharma, pursuant a Master Services Agreement, for the non-exclusive manufacture and supply of product.

The agreement was executed in April 2019 with an initial three year term and automatically renews at the end of the current term for an indefinite period unless we provide written notice of termination to Haupt Pharma no later than 60 days prior to the expiration of the initial term.

After the initial term, either party may terminate the agreement without cause with at least 12 months’ notice.

Additionally, if a party materially breaches certain obligations under the agreement and does not cure such breach within 30 days of receiving notice of the breach from the non-breaching party, the non-breaching party may terminate the agreement immediately upon written notice to the breaching party.

Either party may also terminate the agreement with immediate effect if the other party breaches certain specified obligations as set forth in the agreement.

Product Candidates

Similar to DTX301, the drug substance and drug product for DTX401 are manufactured on a non-exclusive basis by a contract manufacturing organization, or CMO, pursuant to cGMP requirements.

DTX401 is currently manufactured using HEK293 suspension mammalian cells.

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As the clinical program advances we may consider alternate cell manufacturing systems such as HeLa cell systems.

The drug substance and drug product for DTX301, our AAV product candidate, are manufactured on a non-exclusive basis by a CMO, pursuant to cGMP requirements.

DTX301 is currently manufactured using HEK293 mammalian cells.

HEK293 cells are straightforward to grow and transfect readily, and as a result, are widely used in the biotechnology industry to produce therapeutic proteins and viral vectors for gene therapy on a small scale.

As we advance and scale up our processes for Phase 3 clinical and commercial scale manufacturing, we intend to transition to a cell-based suspension bioreactor format.

Commercialization and Product Support

We have built our own commercial organizations in North America, Europe and Latin America to effectively support the commercialization of our products and product candidates, if approved, and we expect to expand on these efforts.

Our intention is to expand our product portfolio and its geographic scope, whether via acquisition, strategic partnerships, or through the continued development of our proprietary pipeline.

We may elect to utilize strategic partners, distributors, or contract management organizations to assist in the commercialization of our products.

The commercial infrastructure for rare disease products typically consists of a targeted, specialty field organization that educates a limited and focused group of physicians supported by field management and internal support teams, which includes our patient support services hub and distribution team.

Our intention is to expand our product portfolio and its geographic accessibility, whether via acquisitions, strategic partnerships, or through the continued development of our proprietary pipeline.

We may elect to utilize strategic partners, distributors, or contract management organizations to assist in the commercialization of our products in certain geographies.

One challenge, unique to commercializing therapies for rare diseases, is the difficulty in identifying eligible patients due to the very small and sometimes heterogeneous disease populations.

Our management team focuses on maximizing patient identification for both clinical development and commercialization purposes in rare diseases.

Additional capabilities important to the rare disease marketplace include the management of key stakeholders such as managed care organizations, group-purchasing organizations, specialty pharmacies, and government accounts.

Our commercial and medical affairs teams focus on maximizing patient identification for both clinical development and commercialization purposes in rare diseases.

To develop the appropriate commercial infrastructure, we will have to invest a significant amount of financial and management resources, some of which will be committed prior to regulatory approval of the products that they are intended to support.

We continue to build a medical affairs organization and multiple capabilities across North America, Europe, Turkey, and Latin America to meet the scientific educational needs of the healthcare providers and patients in the rare disease community, focusing on providing accurate disease state and balanced product information across our portfolio for appropriate management of patients with rare disorders.

We continue to build a medical affairs organization and other capabilities across North America, Europe, Turkey, and Latin America to meet the scientific educational needs of the healthcare providers and patients in the rare disease community, focusing on providing accurate disease state information and balanced product information across our portfolio for appropriate management of patients with rare disorders.

Medical affairs is comprised of the following capabilities in support of our mission:

medical information, patient advocacy, patient diagnosis, medical science liaisons, research and educational grants.

medical information, patient advocacy, patient diagnosis liaisons, medical science liaisons, research and educational grants.

Medical affairs will engage as early as Phase 1 and will continue work throughout the lifecycle of each product and product candidate as dictated by the specific scientific needs in each therapeutic area.

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Accordingly, our operations are and will be subject to a variety of regulations and other requirements, which vary from country to country.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local, and foreign statutes and regulations require the expenditure of substantial time and financial resources.

Global Regulation of Clinical Studies

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These and other laws govern our use, handling and disposal of various biological and chemical substances used in, and waste generated by, our operations.

Complying with these requirements may have a significant impact on our capital expenditures and results of operations.

Our customers include collaboration partners, drug wholesalers, and retail pharmacy distributors .

For the year ended December 31, 2019, 80% of our total revenues were generated under our collaboration agreement with KKC.

As of December 31, 2019, we had 740 full-time employees.

None of our employees is represented by labor unions or covered by collective bargaining agreements.

We consider our relationship with our employees to be good.

For the year ended December 31, 2020, more than half of our total revenues were generated under our collaboration agreement with KKC.

Human Capital

As of December 31, 2020, we had 893 total employees, of which 613 are in research and development and 280 are in sales, general, and administrative.

Further, 825 are based out of the United States, including facilities at Novato, California, Brisbane, California, Cambridge, Massachusetts, and Woburn, Massachusetts, and 68 are based out of our international locations.

The majority of new employees hired during the year ended December 31, 2020 were to support and extend our clinical and preclinical pipeline as well as our commercialization activities, with hires in commercial, clinical development and operations, research, manufacturing, and general and administrative functions.

We believe our relationship with our employees to be generally good.

We have not experienced any material employment-related issues or interruptions of services due to labor disagreements and are not a party to any collective bargaining agreements.

We expect to continue to add employees in 2021 with a focus on expanding our in-house manufacturing capacity through construction of our gene therapy manufacturing facility, as well as increasing expertise and bandwidth in clinical and preclinical research and development and commercialization activities.

The Company continually evaluates the business need and opportunity and balances in house expertise and capacity with outsourced expertise and capacity.

Currently, we outsource substantial clinical trial work to clinical research organizations and certain drug manufacturing to contract manufacturers.

We maintain a safety culture grounded on the premise of eliminating workplace incidents, risks and hazards.

In response to COVID-19, we have implemented and continue to enhance safety measures in all our facilities, including:

Adding work from home flexibility for our workforce;

Reducing density and increasing physical distancing in workspaces for essential employees working onsite;

Establishing clear and regular COVID-19 policies, safety protocols, and updates to all employees;

Increasing cleaning and sanitization protocols across all locations;

Providing additional personal protective equipment and cleaning supplies;

Implementing protocols to address actual and suspected COVID-19 cases and potential exposure;

Providing routine COVID-19 testing for essential employees working onsite;

Implementing daily health attestations and capacity management via online app;

Including healthcare professionals on staff to administer testing and a health declaration process;

Prohibiting all domestic and international non-essential travel for all employees; and

Requiring face coverings to be worn in all locations.

We believe our company’s success depends on our ability to attract, develop and retain key personnel.

We invest in the growth and development of our employees through various training and development programs that build and strengthen employees’ leadership and professional skills, including leadership development programs for new leaders which continued virtually during the pandemic.

We also have a talent management framework and process in place that regularly conducts activities like performance management, succession and workforce planning in order to support our employees in their growth and development and ensure we provide learning opportunities.

To continually assess and improve our employee retention and engagement, we conduct an engagement survey on an annual basis, the results of which are discussed with our board of directors, at all hands employee meetings and in individual functions.

We take actions to address areas of employment concern and follow-up routinely to share with employees what we are doing.

Retention of our key contributors and the results from our annual engagement survey were also included as our corporate goals for fiscal year 2020 and as part of our corporate goals for 2021.

We strive toward having a diverse team of employees and are committed to equality, inclusion and workplace diversity.

To accomplish this, we have included questions in our engagement survey to measure employee perception of inclusive culture.

Business units review diversity data related to hiring, promotions, and retention on an ongoing basis.

In 2020, we established an Inclusion and Diversity Action Team (I&D Action Team) comprised of 11 employee representatives throughout our company.

Amongst other initiatives, our I&D Action Team engages in continual discussions across the various business functions to identify potential actions to address areas of improvement and is focused on building accountability across the organization to ensure we meet our diversity objectives.

General Information

We were incorporated in California in April 2010 and reincorporated in Delaware in June 2011.

Our principal executive offices are located at 60 Leveroni Court, Novato, California 94949.

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You are advised to read this Annual Report in conjunction with other reports and documents that we file from time to time with the Securities and Exchange Commission, or SEC.

In particular, please read our definitive proxy statements, our Quarterly Reports on Form 10-Q and any Current Reports on Form 8-K that we may file from time to time.

In particular, please read our definitive proxy statements, our Annual Reports on Form 10-K, our Quarterly Reports on Form 10-Q and any Current Reports on Form 8-K that we may file from time to time.

The SEC maintains information for electronic filers (including Ultragenyx) at its website at www.sec.gov .

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business