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Burosumab - Kyowa Hakko Kirin Pharma/Ultragenyx Pharmaceutical

Drug Profile

Burosumab - Kyowa Hakko Kirin Pharma/Ultragenyx Pharmaceutical

Alternative Names: Anti-FGF23 monoclonal antibody; Anti-fibroblast growth factor 23 monoclonal antibody; burosumab-twza; Crysvita; FGF23; KRN-23; UX 023

Latest Information Update: 09 Sep 2021

At a glance

  • Originator Kyowa Hakko Kirin
  • Developer Kyowa Hakko Kirin; Kyowa Kirin; Ultragenyx Pharmaceutical
  • Class Monoclonal antibodies; Skin disorder therapies
  • Mechanism of Action Fibroblast growth factor 23 inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    Yes - X-linked dominant hypophosphataemic rickets; Osteomalacia
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed Osteomalacia; X-linked dominant hypophosphataemic rickets
  • Phase II Nevus

Most Recent Events

  • 07 Sep 2021 Registered for Osteomalacia (In adults) in Canada (SC)
  • 06 Aug 2021 Registered for X-linked dominant hypophosphataemic rickets in Singapore (SC) prior to August 2021 (Kyowa Hakko Kirin pipeline, August 2021)
  • 06 Aug 2021 Registered for X-linked dominant hypophosphataemic rickets in South Africa (SC) prior to August 2021 (Kyowa Hakko Kirin pipeline, August 2021)

Development Overview

Introduction

Burosumab (previously KRN 23) is a fully human recombinant IgG1 monoclonal antibody targeting phosphaturic hormone fibroblast growth factor 23 or FGF 23 (or phosphatonin), being developed by Kyowa Kirin (formerly Kyowa Hakko Kirin) and Ultragenyx, for the treatment of X-linked dominant hypophosphataemic rickets (XLH), epidermal nevus syndrome (ENS) and tumour-induced osteomalacia (TIO). FGF 23 reduces serum levels of phosphorus and vitamin D by regulating phosphate excretion and vitamin D production by the kidney. Phosphate wasting in XLH and TIO is caused by excessive levels and activity of FGF 23. Burosumab binds to FGF 23 rendering it inactive, and thereby leading to an increase in kidney tubular absorption of phosphate and an increased vitamin D production. Burosumab subcutaneous formulation is launched for the treatment of XLH, in the US, Canada and Turkey, Netherlands and Poland, France, Greece and United Kingdom. It is conditionally approved in the EU, Norway, Iceland and Liechtenstein, and has been approved in Japan, Canada, Brazil, United Arab Emirates, Hong Kong, China, Oman, Israel and Switzerland, for the treatment of X-linked dominant hypophosphataemic rickets and osteomalacia. It is approved in China for XLH and osteomalacia, approved in Bahrain, Singapore, South Africa for XLH, under regulatory review in Australia, Thailand and Malaysia for XLH. Candidate is under regulatory review in European Union and South Korea for osteomalacia. It is also available for the treatment of osteomalacia, in the US and approved in Japan. It is also approved in EU, Norway, Iceland and Liechtenstein for adults X-linked dominant hypophosphataemic rickets. Candidate is under regulatory review for X-linked dominant hypophosphataemic rickets in Kuwait, Colombia, South Korea and Taiwan. Clinical development for nevus and X-linked dominant hypophosphataemic rickets is ongoing in multiple countries. Burosumab injection is approved for adult patients in Canada.

Kyowa Hakko Kirin was also developing an intravenous formulation of the antibody, however, the development appears to have been discontinued for this formulation.

In July 2019, Kyowa Hakko Kirin changed its name to Kyowa Kirin [1] .

Company Agreements

In December 2019, Ultragenyx Pharmaceutical entered into an agreement with Royalty Pharma, according to which Ultragenyx Pharmaceutical sold $US320 million a royalty right due to Ultragenyx from Kyowa Kirin Co. Ltd for the net sales of Crysvita® (burosumab) in the European Union, the United Kingdom and Switzerland to Royalty Pharma. The agreement will automatically expire in the event aggregate royalty payments received by Royalty Pharma are equal to or greater than 1.9 times the purchase price prior to December 31, 2030, or in the event aggregate royalty payments are equal to or greater than 2.5 times the purchase price if the prior threshold is not met by the end of 2030. Once the threshold amount has been met, the EU, UK, and Switzerland royalty payments will revert back to Ultragenyx [2]

In May 2017, Ultragenyx entered into an agreement with Kyowa Hakko Kirin, whereby Ultragenyx was granted the right to commercialise burosumab in Turkey and will have the option to take over commercialization efforts after a certain minimum period. [3]

Kyowa Hakko Kirin entered into a collaboration and license agreement with Ultragenyx Pharmaceutical in August 2013, to develop and commercialise burosumab. Under the terms of the agreement, the companies will co-develop the antibody in the US, the EU and Canada, with Ultragenyx leading development activities in the XLH indication. If the product is approved, the companies will share commercial responsibilities and profits in the US and Canada. Kyowa Kirin will commercialise burosumab in the EU, and Ultragenyx will develop and commercialise the product in Mexico, Central and South America. Kyowa Kirin will manufacture and supply burosumab globally [4] .

Key Development Milestones

X-linked dominant hypophosphataemic rickets (XLH)

In September 2019, the US FDA approved label expansion for burosumab to include new clinical data demonstrating superiority of treatment with burosumab versus oral phosphate and active vitamin D (conventional therapy) in paediatric patients with XLH, and improvement in stiffness, and maintenance of efficacy of burosumab in adult patients with longer-term treatment. The indication has been expanded to include infants as young as six months of age [5] . In April 2018, Ultragenyx Pharmaceutical and Kyowa Hakko Kirin announced that the US Food and Drug Administration (FDA) had approved burosumab (Crysvita®) for the treatment of X-linked hypophosphatemia (XLH) in adult and paediatric patients, one year of age and older. The product was subsequently launched in the US [6] . In October 2017, the US FDA had accepted a Biologics License Application (BLA), seeking approval for the treatment of adult and paediatric patients with XLH, and had granted a priority review status to the application. The FDA had assigned a (PDUFA) action date of April 17, 2018 [7] . In August 2017, Ultragenyx had submitted the BLA to the FDA [8] . In June 2017, Ultragenyx Pharmaceutical announced that it reached an agreement with the FDA at a Pre-Biologics License Application meeting on the clinical package to support the burosumab BLA filing for XLH. At the meeting, the FDA agreed that the BLA can be submitted based on available clinical data and confirmed that both paediatric and adult indications would be included in the review. Specifically, for the paediatric XLH population, the FDA agreed that the 64-week data from Study CL201 in 5 - 12 year old patients and 24-week data from Study CL205 in 1 - 4 year old patients would be sufficient for review. The FDA confirmed that data from the paediatric phase III trial (CL301) would not be required for the BLA filing. To support the adult XLH indication, the FDA agreed that the review would be based on the totality of the data from the adult phase III trial (CL303) including fracture healing data, and bone biopsy data from the 48-week phase III trial (CL304) in adults [9] . In November 2017, the company reported that it did not intend to conduct an advisory committee meeting to discuss the BLA [9] [10] [11] . The Office of Orphan Drug Development (OOPD) of the US FDA granted rare paediatric disease designation to burosumab for the treatment of X-linked hypophosphataemic rickets [3] [12] . Kyowa Kirin, in December 2019, submitted a supplemental biologics license application in the US, seeking the approval of burosumab, for the treatment of tumor-induced osteomalacia [13] .

In July 2021, Kyowa Kirin announced that the burosumab (CRYSVITA®) has been approved for the option of self-administration in the European Union (EU) for the treatment of X-linked hypophosphataemia (XLH). The approval means that some patients or carers may be suitable to administer CRYSVITA themselves, at the recommendation of the treating physician, in its licensed indication for the treatment of XLH in children and adolescents aged 1 to 17 years with radiographic evidence of bone disease, and in adults [14] . Earlier in May 2021, Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended that CRYSVITA® (burosumab) be approved for the option of self-administration for the treatment of X-linked hypophosphataemia (XLH). The Committee indicated that, in addition to healthcare professionals, some patients or carers may be suitable to administer burosumab, at the recommendation of the treating physician in its licensed indication for the treatment of XLH in children and adolescents aged 1 to 17 years with radiographic evidence of bone disease, and in adults. Company expects final decision on the application to add the option of self-administration of burosumab to the current approved SmPC is expected in the coming months [15] . In October 2020, the European commission granted marketing authorization to burosumab, for the treatment of X-linked hypophosphatemia (XLH) in older adolescents and adults. The approval was based on data from the phase III UX023-CL303 and UX023-CL304 trials [see below] [16] . In February 2018, the European commission granted conditional marketing authorisation to burosumab, for the treatment of X-linked hypophosphatemia (XLH) with radiographic evidence of bone disease in children 1 year of age and older and adolescents with growing skeletons [17] . The approval follows a positive opinion adopted by the CHMP, in December 2017, recommending the conditional marketing authorisation of burosumab, for the treatment of paediatric XLH. The conditional authorization required fulfilment of specific obligations related to the completion of ongoing clinical studies of burosumab in paediatric patients, and was based on efficacy results from two phase II studies [18] [19] [20] . In December 2016, Ultragenyx and Kyowa Hakko Kirin announced the submission of the conditional marketing authorisation application (MAA) and acceptance of the application by the EMA for burosumab for the treatment of XLH in paediatric population. To ensure the expeditious availability of burosumab for paediatric XLH patients in Europe and to avoid any potential delays in the review procedure due to the large amount of recent data from the adult XLH phase III study to be filed, Kyowa Hakko Kirin and Kyowa Kirin International (a wholly owned subsidiary of Kyowa Hakko Kirin) have decided to separate the adult and paediatric indications. A filing for the adult indication is planned after a decision is first reached on the paediatric indication [21] [22] [23] [24] [25] . In July 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the expanded approval of burosumab to include older adolescents and adults living with the rare disease X-linked hypophosphataemia (XLH). The CHMP recommends that this approval is expanded to include all adolescents with radiographic evidence of bone disease, regardless of growth status, as well as adults with XLH. The CHMP opinion will now be reviewed by the European Commission, with a final decision expected in the second half of 2020. The positive opion is based on phase III UX023-CL303 and UX023-CL304 trial [see below]Earlier in November 2019, a regulatory application submitted in the EU was accepted for review, seeking the approval of burosumab, for the treatment of adult XLH [26] [27] [13] .

As of August 2021, burosumab was approved and subsequently launched for X-linked dominant hypophosphataemic rickets in Signapore and South Africa (Kyowa Kirin's pipeline, August 2021)

As of May 2021, burosumab was approved and subsequently launched for X-linked dominant hypophosphataemic rickets in United Kingdom, France, Greece, Netherlands, Poland.

As at May 2021, burosumab was approved for X-linked dominant hypophosphataemic rickets in Bahrain and regulatory applications were submitted in Australia, South Africa, Singapore, Thailand and Malaysia [28]

As at June 2020, burosumab was approved for X-linked dominant hypophosphataemic rickets in China, Oman and Hong Kong. Kyowa Kirin, as at December 2019, had submitted regulatory applications in China seeking the approval of burosumab, for the treatment of FGF23-related hypophosphataemic rickets (X-linked dominant hypophosphataemic rickets)(Kyowa Kirin's pipeline, August 2020) [13] .

In February 2020, Kyowa Kirin reported that burosumab has been approved by Swissmedic, for the treatment of adults and children (1 year of age and above) with X-linked hypophosphatemia [29] .

In February 2020, the Scottish Medicines Consortium (SMC) will assess burosumab within the ultra-orphan pathway in Scotland. Ultragenyx will now provide plans describing further data on the effects of the drug, including those on the patient and carer lived experience, will be collected. Burosumab will then be available on the NHS in Scotland for a period of three years while this information is gathered. After this, SMC will review the evidence and make a decision on routine availability in NHSScotland [30] .

Prior to March 2019, Kyowa Hakko Kirin reported that burosumab was approved for the treatment of X-linked hypophosphatemia (XLH) in the United Arab Emirates and Israel (Kyowa Hakko Kirin pipeline, July 2019).

Health Canada, in December 2018, approved burosumab injection, for the treatment of X-linked hypophosphatemia (XLH) in paediatric and adult patients, aged one year and older. The approval for paediatric and adult patients was based chiefly, on positive data from studies CL201 and CL303 [see below], respectively. Data from studies CL205 and CL304 [see below], also contributed to the approval. The regulatory application was filed earlier, in May 2018, by Kyowa Hakko Kirin [31] [32] .

In September 2019, the Japan's Ministry of Health, Labor and Welfare (MHLW) approved burosumab (Crysvita®) for the treatment of FGF23-related hypophosphatemic rickets and osteomalacia. The application for manufacturing and marketing approval was filed by Kyowa Hakko Kirin in January 2019 [33] [34] .

Prior to September 2019, burosumab received orphan drug designation by the Ministry of Health, Labor and Welfare (MHLW) in Japan for FGF23-related hypophosphatemic rickets and osteomalacia [33] .

In March 2019, Brazil’s National Health Surveillance Agency (ANVISA) approved burosumab (Crysvita®) for the treatment of X-linked hypophosphatemia in adult and pediatric patients, aged one year and older. The approval noted to be the first Crysvita® approval in Latin America [35] . Earlier, in November 2018, Ultragenyx submitted regulatory applications in Brazil and Columbia, seeking approval of the product [36] .

Kyowa Kirin, as at December 2019, had submitted regulatory applications in South Korea, seeking the approval of burosumab, for the treatment of FGF23-related hypophosphataemic rickets and osteomalacia [13] .

In June 2016, the US FDA granted Breakthrough Therapy Designation to burosumab for the treatment of XLH in paediatric patients one year of age and older [37] .

In September 2018, Kyowa Hakko Kirin reported that the company has initiated an expanded-access programme for X-linked hypophosphataemia in the UK [38] .

In September 2018, The National Institute for Health and Care Excellence (NICE) adopted a positive opinion recommending the use of burosumab, for the treatment of X-linked hypophosphataemia in children and young people with growing bones in England and Wales. The final guidance is expected to be published on 24th October 2018 [38] .

In November 2018, Ultragenyx reported initiation of reimbursed named patient treatment in Argentina in response to physician requests [36] .

Prior to March 2019, Kyowa Hakko Kirin reported that it has filed regulatory applications for the approval of burosumab for the treatment of X-linked hypophosphatemia (XLH) in Taiwan, Kuwait and Switzerland (Kyowa Hakko Kirin pipeline, July 2019).

In October 2018, Kyowa Hakko Kirin initiated a phase IIIb trial to assess the safety and efficacy of burosumab in patients with with X-linked dominant hypophosphataemic rickets (EudraCT2018-000202-37). The open label study intends to enrol approximately 40 patients in France [39] .

Kyowa Hakko Kirin, in July 2017, initiated a phase III trial to assess the efficacy and safety of burosumab in paediatric patients with X-linked dominant hypophosphataemic rickets and osteomalacia (NCT03233126; KRN23-003; JapicCTI-173614). This open-label trial is designed to enrol approximately 10 patients in Japan [40] .

In April 2017, Ultragenyx announced that its phase III trial met its primary endpoint of increasing serum phosphorus levels as 94% of patients treated with burosumab (n = 68) achieved serum phosphorus levels above the lower limit of normal and maintained levels in the low normal range through 24 weeks, compared to 8% in the placebo arm (UX023-CL303; NCT02526160). Ultragenyx completed the phase III trial in adult patients with X-linked Hypophosphatemia, in December 2016. The randomised, double-blind, placebo-controlled trial, in July 2016, completed enrolment of 134 patients in the US, Canada, Denmark, France, Ireland, Italy, Japan, the UK and South Korea [41] . The trial was initiated following discussions with the EMA and US FDA. In September 2019, the company presented the final efficacy and adverse events data at the 41st Annual Meeting of the American Society for Bone and Mineral Research (ASBMR-2019). In March 2020, the results from the trial were presented at the 102nd Annual Meeting of the Endocrine Society (ENDO-2020) [42] [43] [44] [45] [46] [25] [47] .

In December 2019, Ultragenyx Pharmaceutical and Redwood Dermatology Sciences completed a phase III trial to assess the safety and efficacy of burosumab, in a single paediatric patient with Epidermal Nevus Syndrome (ENS) and associated hypophosphatemic rickets (ENSKRN23-1; NCT03581591). The open-label trial was initiated in January 2018 and enrolled one patient in the US [48] .

In December 2018, Ultragenyx and Kyowa Hakko Kirin completed a phase III trial that evaluated the effect of burosumab on underlying osteomalacia using bone biopsy (UX023-CL304; NCT02537431). The open label trial was initiated in December 2015, and enrolled 14 patients in the US, Canada, Denmark, France, Japan, and South Korea. In May 2017, the company released interim data from the trial. The company also intends to discuss the clinical data with regulatory authorities. Updated results from the trial were released in November 2017 [9] [49] [50] .

In July 2019, Ultragenyx Pharmaceuticals completed the phase III PIXLES trial that met its primary endpoint of superior improvement in rickets in children with XLH treated with burosumab over conventional oral phosphate and active vitamin D therapy (UX023-CL301; EudraCT2016-000600-29; NCT02915705). The trial evaluated the efficacy and safety of burosumab, in children with XLH (aged 1 to 12 years) who have radiographic evidence of rickets and open epiphyses. The randomised, open label trial was initiated in September 2016, and enrolled 61 patients in the US, Australia, Canada, Germany, Denmark, Ireland, Japan, Spain, South Korea, the UK, Italy and Sweden. Earlier, the US FDA recommended the inclusion of a control arm for non-inferiority comparison. Ultragenyx Pharmaceutical released top-line results of the trial in May 2018. In February 2019, Ultragenyx and Kyowa Kirin announced the 64 weeks safety and efficacy data. Additional 40 weeks safety data was presented at the 101st Annual Meeting of the Endocrine Society. In March 2020, updated data was presented at the 102nd Annual Meeting of the Endocrine Society (ENDO-2020) [51] [52] [53] [54] [24] [55] [56] [57] .

In September 2019, Ultragenix Pharmaceutical completed a phase II trial that evaluated the safety, pharmacodynamics and efficacy of burosumab SC injection q2w in paediatric patients with X-linked dominant hypophosphataemic rickets (UX023-CL205; NCT02750618). The open-label, single-group trial was initiated in May 2016, and enrolled 13 patients (1 - 4 years) in the US. In April 2017, Ultragenix Pharmaceutical released interim results for the trial. In March 2021, updated efficacy and safety data from the trial were presented at the 103rd Annual Meeting of the Endocrine Society (ENDO-2021) [58] [9] [59] [60] .

In October 2018, Ultragenyx and Kyowa Hakko Kirin completed a phase II trial that evaluated the pharmacodynamics and safety of burosumab in paediatric subjects with XLH along with the clinical effects of drug on bone health and deformity (UX023-CL201; NCT02163577; EudraCT2014-000406-35). Evaluation of the change from baseline in the severity of rickets as measured by Rickets Severity Score (RSS) total score was the primary endpoint of the trial. The open label trial was initiated in July 2014. Ultragenyx completed patient enrolment in the US, the UK, France and the Netherlands, in November 2014. Interim results from 36 patients through 40 weeks of treatment were announced in December 2015. Previously, positive interim 16-week data were announced in the first half of 2015 and additional data from the first 12 patients enrolled in the study was released by Ultragenyx in July 2015. The protocol was previously reviewed and accepted by the US FDA, the UK MHRA and the Dutch Medicines Evaluation Board [24] [61] [55] [4] [25] [62] [63] [64] [65] [66] . In April 2016, the company presented interim safety and efficacy data from this study at The 98th Annual Meeting of the Endocrine Society (ENDO-2016) [67] . Updated results were released by the company in April 2017 and September 2016 [59] [68] . Later, in September 2019, results from the trial were presented at 41st Annual Meeting of the American Society for Bone and Mineral Research (ASBMR-2019) [69] .

In October 2019, Kyowa Kirin initiated a phase I/II trial to investigate the safety, tolerability, pharmacokinetics and efficacy of burosumab, in the treatment of patients from birth to one year of age, afflicted with X-linked dominant hypophosphataemic rickets (EudraCT2019-000469-19; BUR-CL207). The open label, non-randomised trial intends to enrol approximately 20 paediatric patients, in Sweden, Germany, Austria, and France [70] .

Kyowa Hakko Kirin completed an open-label, uncontrolled phase I/II trial in adult patients with XLH in October 2013 (KRN23-INT-001; NCT01340482). The trial aimed to assess the safety and efficacy of multiple, escalating doses of subcutaneous burosumab. Patients were dosed every 28 days, up to four doses. The trial initiated the recruitment of 29 patients in the US and Canada, in April 2011 [71] . Results from this phase I/II trial were presented at the Joint meeting of the 16th International Society of Endocrinology and the 96th Annual Meeting of the Endocrine Society (ICE/ENDO-2014) [72] [73] [74] [75] . A 12-month, open-label extension phase I/II trial was initiated in February 2012 (KRN23-INT-002; NCT01571596). The study enrolled 23 patients from the US and Canada. Cumulative results from INT-001 and INT-002 studies were presented at the Annual Meeting of the American Society of Bone and Mineral Research in September 2014 (ASBMR-2014) [76] [77] [72] [73] [78] . In September 2018, the companies completed a phase IIb extension study that evaluated the long-tern safety and pharmacodynamics of burosumab, in patients with XLH (NCT02312687; UX023-CL203). The open-label study was initiated in March 2015, and enrolled 20 patients, who participated in Study KRN23-INT-001 or Study KRN23-INT-002, in the US [79] . Interim results from 20 patients were released by the company in September 2016 [68] .

In December 2015, Kyowa Hakko Kirin completed a phase I trial which assessed the safety and tolerability of a subcutaneous dose of burosumab (0.3 mg/kg, 0.6 mg/kg or 1 mg/kg) in patients with XLH (KRN23-001; NCT02181764). The open-labelled trial initiated in July 2014, enrolled 15 patients in Japan and South Korea [80] [81] .

In December 2011, Kyowa Hakko Kirin completed a first-in-human, randomised, double-blind, placebo-controlled phase I trial to assess the safety and tolerability of burosumab after a single intravenous and subcutaneous dose in patients with XLH (US-02; KRN23US02; NCT00830674). The dose-escalation trial enrolled 38 adult patients in the US, and results were reported in October 2013 [82] [83] [84] .

Burosumab was granted the orphan drug status for the treatment of X-linked dominant hypophosphataemic rickets in the EU in October 2014, and in the US in December 2009 [85] .

Epidermal nevus syndrome (ENS)/tumour-induced osteomalacia (TIO)

In January 2019, Kyowa Hakko Kirin filed an application for manufacturing and marketing approval with Japan's Ministry of Health, Labor and Welfare (MHLW) for burosumab for the treatment of osteomalacia. Feedback from MHLW is expected around September 2019 [34] .

As of October 2020, burosumab (Crysvita®) is available in the US for the treatment of fibroblast growth factor 23 (FGF23)-related hypophosphatemia in tumour-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localised in adults and pediatric patients 2 years of age and older. In June 2020, the same was approved by the US FDA based on data from two single-arm phase II studies [See below]. As of May 2020, US FDA accepted sBLA of burosumab for review and has set a Prescription Drug User Fee Act (PDUFA) date of June 18, 2020. Company has also announced that US FDA has not indicated requirement of any inspection for completion of the review [86] [87] [88] . Earlier in December 2019, Ultragenyx Pharmaceutical announced submission of the sBLA to the US FDA. In September 2019, Ultragenyx Pharmaceutical announced the completion of a pre-sBLA meeting with the US FDA and agreement on the filing package and a sBLA submission is planned for the first half of 2020 [89] [90] .

As at May 2021, burosumab was approved for tumour-induced osteomalacia in China and Bahrain and regulatory applications were submitted in the European Union and Canada [28]

In September 2021, Ultragenyx Pharmaceutical announced that the Health Canada approved burosumab injection (Crysvita™) for the treatment of tumour induced osteomalacia for adult patients in Canada [91] .

In November 2018, Ultragenyx reported that discussions were ongoing with the US FDA regarding regulatory pathway for burosumab (SC) for treatment of tumour-induced osteomalacia [36] .

In January 2021, Ultragenyx, in collaboration with Kyowa Hakko Kirin completed a phase II trial that evaluated the efficacy and safety of burosumab administered via subcutaneous injections once every 4 weeks, in adult patients with ENS or TIO (UX023T-CL201; NCT02304367). The open-label trial was initiated in March 2015, and enrolled 17 patients in the US [92] [62] [93] [94] . In April 2016, Ultragenyx announced interim safety and efficacy data for the first eight patients including one patient with epidermal nevus syndrome. Updated interim data demonstrating improved serum phosphorus levels and bone metabolism measures for burosumab were reported in September 2016 [95] [96] . Interim results for burosumab were also presented at the 38th Annual Meeting of the American Society for Bone and Mineral Research-2016 (ASBMR-2016). Updated 48-week and 72 week results from the trial were presented at the 40th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR-2018) [36] [9] [97] . Additional 48-week results from the trial were presented at the 101st Annual Meeting of the Endocrine Society (ENDO-2019) [98] . Updated 144 week results from the trial were released by the company, in June 2020 [87] [99] . In March 2020, week 144 results from the trial were presented at the 102nd Annual Meeting of the Endocrine Society (ENDO-2020) [100] .

Kyowa Hakko Kirin initiated a phase II trial in April 2016, to assess the efficacy and safety of burosumab after its 48-week q4w repeated SC injection in patients with ENS or TIO (KRN23-002; NCT02722798). The open-label, single-group, intra-individual dose adjustment trial enrolled 13 patients in Japan and South Korea [101] . In June 2020, the company released the results from the trial [87] [99] .

In June 2017, burosumab was granted orphan drug designation by the US FDA for the treatment of tumour-induced osteomalacia [102] .

Financing information

In July 2014, Ultragenyx Pharmaceutical initiated an underwritten public offering of 2 017 349 shares of its common stock, comprising of 1 311 277 shares offered by Ultragenyx and 706 072 shares to be offered by existing shareholders. Shares were priced at $US40.00 per share before underwriting discounts. The company planned to use proceeds from the offering to support clinical and preclinical development of product candidates, including potential new formulations of, or indications for its existing product candidates [103] .

Patent Information

Ultragenyx has rights to several patents and pending applications, in the US and ex-US from Kyowa Hakko Kirin Pharma, related to burosumab. These include six issued US patents, due to expire between 2022 to 2035, as well as issued patents outside the US, with validity between 2021 and 2035. In relation to composition of matter patents, applications have been submitted seeking extension of patent term in the US from 2029 to 2032, and in Europe from 2028 to 2033. In addition, the candidate has protection in the US by regulatory exclusivity until 2030, and by orphan drug exclusivity for treatment of tumor-induced osteomalacia and X-linked hypophosphatemia until 2027 and 2025, respectively [104] .

Drug Properties & Chemical Synopsis

  • Route of administration IV, SC
  • Formulation Injection
  • Class Monoclonal antibodies, Skin disorder therapies
  • Target Fibroblast growth factor 23
  • Mechanism of Action Fibroblast growth factor 23 inhibitors
  • WHO ATC code

    D11A-X (Other dermatologicals)

    M05B-X05 (Burosumab)

  • EPhMRA code

    D11A (Other Dermatological Preparations)

    M5 (Other Drugs for Disorders of the Musculo-Skeletal System)

  • Chemical name Immunoglobulin G1-kappa, anti-(human Fibroblast growth factor 23 (FGF-23, Phosphatonin, Tumor-derived hypophosphatemia-inducing factor)); human monoclonal antibody: gamma1 heavy chain (1-447) (human VH (human IGHV1-46*01 (95%) -(IGHD)-IGHJ3*02 (94%)) (8.8.10) (1-117) -human IGHG1*01 (118-447)) (220-213')-disulfide with kappa light chain (1'-213') (human V-KAPPA (human IGKV1D-13*01 (98%) -IGKJ3*01) (6.3.8) (1'-106') human IGKC*01 (107'-213')) dimer (226-226'':229-229'')-bisdisulfide
  • Molecular formula C6388 H9904 N1700 O2006 S46
  • CAS Registry Number 1610833-03-8

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

nevus

not specified

Osteocalcin

Alkaline phosphatase

1

1

nevus

Inclusion

FGF23

1

nevus

Outcome Measure

PINP

FGF23

CTx

1

1

1

osteomalacia

not specified

Osteocalcin

Alkaline phosphatase

1

1

osteomalacia

Inclusion

FGF23

1

osteomalacia

Outcome Measure

PINP

FGF23

CTx

Alkaline phosphatase

2

1

1

1

X-linked dominant hypophosphataemic rickets

Exclusion

PTH

1

X-linked dominant hypophosphataemic rickets

Inclusion

25-Hydroxyvitamin D2

1

X-linked dominant hypophosphataemic rickets

Outcome Measure

PTH

PINP

FGF23

CTx

Ascorbic acid

Alkaline phosphatase

25-Hydroxyvitamin D2

1

3

1

2

1

2

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Burosumab - Kyowa Hakko Kirin Pharma/Ultragenyx Pharmaceutical Alkaline phosphatase not specified
CTx Outcome Measure
FGF23 Inclusion, Outcome Measure
Osteocalcin not specified
PINP Outcome Measure
PTH Exclusion, Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Nevus - - Phase II Japan, South Korea, USA SC / Injection Kyowa Kirin, Ultragenyx Pharmaceutical 01 Apr 2016
Osteomalacia In patients aged 2 years and older In adolescents, In adults, In children Marketed USA SC / Injection Kyowa Kirin, Ultragenyx Pharmaceutical 27 Oct 2020
Osteomalacia - In adults Registered Canada SC / Injection Kyowa Kirin 07 Sep 2021
Osteomalacia - - Registered China, Japan SC / Injection Kyowa Kirin 31 Dec 2020
Osteomalacia - - Preregistration European Union, South Korea SC / Injection Kyowa Kirin 31 Mar 2021
X-linked dominant hypophosphataemic rickets - In children, In infants Marketed United Kingdom SC / Injection Kyowa Kirin, Ultragenyx Pharmaceutical 02 Feb 2021
X-linked dominant hypophosphataemic rickets from infants of six months age -and above children 1 year of age and older and adolescents In adolescents, In adults, In children, In infants Marketed Canada, Turkey, USA SC / Injection Kyowa Kirin, Ultragenyx Pharmaceutical 19 Feb 2019
X-linked dominant hypophosphataemic rickets in patients aged 5 to 12 years In adolescents, In children Marketed Netherlands, Poland SC / Injection Ultragenyx Pharmaceutical 07 Jan 2019
X-linked dominant hypophosphataemic rickets - In adolescents, In adults, In infants, In neonates Marketed France SC / Injection Kyowa Kirin 10 Feb 2020
X-linked dominant hypophosphataemic rickets - - Marketed Greece SC / Injection Kyowa Kirin 25 Aug 2020
X-linked dominant hypophosphataemic rickets - - Registered Bahrain, China, Hong Kong, Israel, Oman, Singapore, South Africa, United Arab Emirates SC / Injection Kyowa Kirin 06 Aug 2021
X-linked dominant hypophosphataemic rickets In adult and pediatric patients, aged one year and older In adolescents, In adults, In children, In infants Registered Brazil SC / Injection Ultragenyx Pharmaceutical 26 Mar 2019
X-linked dominant hypophosphataemic rickets children 1 year of age and older and adolescents In adolescents, In children, In infants Registered European Union, Iceland, Liechtenstein, Norway SC / Injection Kyowa Kirin, Ultragenyx Pharmaceutical 23 Feb 2018
X-linked dominant hypophosphataemic rickets FGF23-related Including older adolescents In adults Registered European Union, Iceland, Japan, Liechtenstein, Norway SC / Injection Kyowa Kirin 02 Oct 2020
X-linked dominant hypophosphataemic rickets in patients 1 year of age and above In adults, In children, In infants Registered Switzerland SC / Injection Kyowa Kirin 25 Feb 2020
X-linked dominant hypophosphataemic rickets - - Preregistration Kuwait, Malaysia, South Korea, Taiwan, Thailand SC / Injection Kyowa Kirin 31 Dec 2020
X-linked dominant hypophosphataemic rickets - - Preregistration Colombia SC / Injection Ultragenyx Pharmaceutical 05 Nov 2018
X-linked dominant hypophosphataemic rickets in patients aged between 1 to 12 years In children, In infants Preregistration Australia SC / Injection Kyowa Kirin, Ultragenyx Pharmaceutical 31 Mar 2021
X-linked dominant hypophosphataemic rickets in patients aged between 1 to 12 years In children, In infants Phase III Japan SC / Injection Kyowa Kirin, Ultragenyx Pharmaceutical 01 Sep 2016
X-linked dominant hypophosphataemic rickets - In adolescents, In children, In infants, In neonates Phase III USA SC / Injection Ultragenyx Pharmaceutical 31 Jan 2018
X-linked dominant hypophosphataemic rickets - In infants, In neonates Phase I/II Austria, Germany, Sweden SC / Injection Kyowa Kirin 18 Dec 2019
X-linked dominant hypophosphataemic rickets - - Discontinued (I) USA IV / Injection Kyowa Hakko Kirin 22 Dec 2017

Priority Development Status

Type Region Indication
BTT USA X-linked dominant hypophosphataemic rickets

Orphan Status

Indication Patient Segment Country Organisation Event Date
Osteomalacia - USA Ultragenyx Pharmaceutical 15 Jun 2017
Osteomalacia - Japan Kyowa Kirin 25 Sep 2019
X-linked dominant hypophosphataemic rickets - USA Ultragenyx Pharmaceutical 14 Dec 2009
X-linked dominant hypophosphataemic rickets - Japan Kyowa Kirin 25 Sep 2019
X-linked dominant hypophosphataemic rickets - European Union Ultragenyx Pharmaceutical 30 Oct 2014

Commercial Information

Involved Organisations

Organisation Involvement Countries
Kyowa Hakko Kirin Originator Japan
Kyowa Kirin Owner Japan
Royalty Pharma Market Licensee European Union, Switzerland, United Kingdom
Ultragenyx Pharmaceutical Market Licensee Turkey
Ultragenyx Pharmaceutical Licensee Canada, Central America, Mexico, South America, USA
National Institutes of Health (USA) Funder USA
Redwood Dermatology Sciences Collaborator USA
Indiana University School of Medicine Collaborator USA

Brand Names

Brand Name Organisations Indications Countries
Crysvita Kyowa Kirin X-linked dominant hypophosphataemic rickets USA, Poland, Canada, Netherlands, European Union

Credit Suisse Market Status

Indication Region Company Phase Expected Launch Year Probability of Success% Patent Expiry Year Expected Generic Entry Last Update
Hypophosphataemia X-Linked (Adults+Pediatric) Europe Kyowa Hakko Kirin, Ultragenyx Marketed 2018 100 2035 - 01 Feb 2021
Hypophosphataemia X-Linked (Adults+Pediatric) ex US, ex EU Kyowa Hakko Kirin, Ultragenyx Marketed 2019 100 - - 01 Feb 2021
Hypophosphataemia X-Linked (Adults+Pediatric) Japan Kyowa Hakko Kirin, Ultragenyx Marketed 2019 100 - - 01 Feb 2021
Hypophosphataemia X-Linked (Adults+Pediatric) US Kyowa Hakko Kirin, Ultragenyx Marketed 2018 100 2035 - 01 Feb 2021

Credit Suisse Financial Forecast

Indication Region 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Last Update
Hypophosphataemia X-Linked (Adults+Pediatric) Europe 0 0 14 69 120 150 185 212 240 250 01 Feb 2021
Hypophosphataemia X-Linked (Adults+Pediatric) ex US, ex EU 0 0 0 10 19 58 88 101 116 128 01 Feb 2021
Hypophosphataemia X-Linked (Adults+Pediatric) Japan 0 0 0 1 37 56 83 93 110 120 01 Feb 2021
Hypophosphataemia X-Linked (Adults+Pediatric) US 0 0 28 232 324 473 615 745 830 875 01 Feb 2021
Total 0 0 42 312 500 737 971 1151 1296 1373

Scientific Summary

  • Adverse Events Frequent: Injection site reactions

Adverse Events

The results from the phase III trial showed that 89% (119/134) of patients completed 96 weeks of treatment and received 1 mg/kg burosumab. To effectively manage hyperphosphatemia (all mild [Grade 1]), protocol-specified dose reductions were required for 11/134 (8.2%) patients. There were no meaningful changes in ectopic mineralization and no neutralising antibodies were observed. No treatment-emergent adverse events led to treatment withdrawal. Burosumab dose reductions effectively managed mild hyperphosphatemia. Earlier, the data from the trial showed that most patients (132/134) experienced an AE. Serious AEs were reported in 22 patients. 92 patients had AEs considered related to treatment by the investigator; most of these were injection site reactions or consistent with burosumab’s safety profile. One of these related-AEs was classified as serious and resolved. Mean (±SE) iPTH level was 96 (±3.8) pg/mL at baseline and progressively declined to 79 (±3.3) pg/mL at Week 96. Nephrocalcinosis score at week 96 changed by 0 in 101 subjects, -1 in 9 subjects, +1 in 10 subjects. There was no difference in the overall frequency of treatment emergent adverse events, treatment related adverse events and serious adverse events between the two treatment groups. The most common (>10%) adverse events in patients treated with either burosumab or placebo were back pain (burosumab 15%, placebo 9%), nasopharyngitis (burosumab 13%, placebo 9%), tooth abscess (burosumab 13%, placebo 8%), injection site reactions (burosumab 12%, placebo 12%), headache (burosumab 12%, placebo 8%), restless legs syndrome (burosumab 12%, placebo 8%), dizziness (burosumab 10%, placebo 6%), nausea (burosumab 10%, placebo 9%), arthralgia (burosumab 9%, placebo 24%), pain in extremity (burosumab 7%, placebo 15%) and oropharyngeal pain (burosumab 2%, placebo 11%). There was no evidence of hypersensitivity reactions to injections. There were two serious adverse events in each treatment group, none of which were considered treatment-related. No differences between groups were observed in serum intact parathyroid hormone levels or ectopic mineralization as assessed by renal ultrasounds or echocardiograms. Of the 134 patients enrolled in the study, one patient in the burosumab arm discontinued treatment during the 24-week double-blind treatment period due to consent withdrawal. There have been no deaths in the study. The safety profile of burosumab at 48 weeks was generally similar to that observed at 24 weeks. The most common adverse events in patients during treatment with burosumab (>10%) were arthralgia (24%), nasopharyngitis (22%), headache (20%), back pain (16%), tooth abscess (13%), fatigue (13%), restless leg syndrome (11%), pain in extremity (11%), pain (11%), toothache (11%), vitamin D deficiency (10%), and musculoskeletal pain (10%). Eleven percent of patients who received burosumab experienced clinical symptoms compatible with hypersensitivity. Fifteen patients experienced serious adverse events (SAEs) during treatment with burosumab, but none of these SAEs were considered treatment-related [42] [43] [47] [41] [44] .

In the phase III PIXLES trial, the safety profile at week 64 was observed to be consistent with data from week 40. Treatment-emergent serious adverse events were not reported with burosumab. There were no study discontinuations or deaths reported with burosumab treatment. Injection site reactions were reported in 51.7% and 45% of patients at week 64 and week 40, respectively, of which all but one were mild and none were serious. Mean serum calcium and serum intact parathyroid hormone levels were not changed in burosumab or conventional therapy arm. Also, no hyperphosphatemia events were observed. No clinical abnormalities were observed in renal ultrasounds pre-and post-treatment in either treatment arm. There were higher pre-defined AEs, including hypersensitivity and injection site reactions, of mild-to-moderate severity in burosumab group. Three SAEs were observed in burosumab group and one in oral phosphate and active vitamin D group, none well treatment related and all were resolved with treatment. Adverse events were including hypersensitivity and injection site reactions, were more frequent with burosumab, and were mild to moderate in severity overall. No discontinuations were occurred. The data was reported from 61 patients enrolled in the trial [51] [56] [52] [53] [57] .

Updated results from 17 patients showed two subjects discontinued, 1 to undergo chemotherapy to treat an AE of neoplasm progression and 1 failed to meet serum phosphorus dosing criteria and therefore received minimal burosumab dosing. There were 16 serious AEs in 7 subjects, all unrelated to drug. Of the 6 subjects with a serious AE of tumor progression/compression, 5 had a history of tumor progression prior to enrollment. There was 1 death, considered unrelated to treatment. In adults with TIO Syndrome, burosumab was associated with improvements in phosphate metabolism, osteomalacia, skeletal metabolism/fracture healing, physical functioning, fatigue, pain, and quality of life [100] . According to updated interim results from 16 patients in a phase II study of burosumab in tumour-induced osteomalacia or epidermal nevus, 44% displayed treatment-related adverse events (TEAEs), which included mild-graded vitamin D deficiency, rash and dysgeusia. Neoplasm progression (tumour progression, thoracic epidural tumor compression, and a mesenchymal tumour progression) was observed as a serious adverse event in one patient with pre-existing metastatic spindle sarcoma, who did not respond and eventually discontinued treatment. There were no injection site reactions, and mean serum calcium, urinary calcium and serum intact parathyroid hormone levels did not show clinically meaningful changes. Two patients had restless leg syndrome, one of whom had symptoms that indicated worsening pre-existing restless leg syndrome. Earlier, interim results did not show incidences of serious adverse events or injection site reactions. Treatment-emergent adverse events (TEAEs) were observed in 87.5% of the patients. TEAEs in two or more patients were musculoskeletal disorders including pain in extremity, arthralgia and musculoskeletal pain. Two of 8 patients experienced mild Vitamin D deficiency and mild rash which were considered as probably related to the study treatment. Two subjects reported worsening of pre-existing restless leg syndrome. Adverse events have been consistent with information previously reported for burosumab [107] [95] [96] [94] . Updated results from 48 weeks and 72 weeks indicated that adverse events generally reflected patients underlying conditions and no serious treatment related adverse events were observed during the trial [36] . At week 72, all 17 patients had more than one AE. In six subjects, there were 13 SAEs, but none were drug-related. Tumour progression was observed in patients with history of tumour progression prior to enrolment. One of the patients discontinued therapy at week 48 for the treatment of tumour progression. One death was observed, but it was considered non-drug related [98] . The most common adverse reactions (>10%) in TIO patients were tooth abscess, muscle spasms, dizziness, constipation, injection site reaction, rash, and headache [87] [99] .

Burosumab was generally safe and well tolerated in a phase II trial in X-linked dominant hypophosphataemic rickets. Mild injection site reactions were the most common treatment related adverse event (AE) reported in 65% of patients. One patient reported fever and muscle pain which was the only possibly treatment related serious AE and it improved without complications. No deaths or discontinuations were indicated in the study. The patients did not indicate any significant changes in serum calcium, urinary calcium and serum intact parathyroid hormone and no patient had serum phosphorus levels above the upper limit of normal in either dosing group. The randomised, open-label, dose-finding study enrolled 52 patients between five and 12 years old, 49 of whom received therapy (oral phosphate/active vitamin D therapy) for an average of approximately seven years prior to entering the study [59] [68] [66] [24] [61] [67] .

Burosumab was well tolerated during the 16 month treatment period, according to cumulative results from a four-week dose escalation study (NCT01340482; INT-001) and a 12-month extension study (NCT01340482; INT-002), in patients with X-linked hypophosphataemic rickets. Injection site reaction, arthralgia, diarrhoea, restless legs syndrome, injection site erythema and pain, upper abdominal pain, headache and reduced neutrophil count were the most commonly reported treatment related adverse events. Renal calculi and restless legs syndrome caused treatment discontinuations in two patients. Mild hypercalcaemia and transient hypercalciuria were observed in two and three patients, respectively. Three subjects had serious adverse events which were deemed unrelated to treatment. No significant changes were observed in parathyroid hormone, renal ultrasound or serum calcium levels. No patient developed anti-burosumab antibodies [77] [76] .

In the phase II adult extension study, most common adverse events were arthralgia (30%), nasopharyngitis (25%), back pain (20%), injection site reaction (20%), and pain in extremity (20%). Mild treatment-related adverse events were reported in 40% patients. None of the four serious adverse events were considered treatment-related with no reported deaths and discontinuations from the study. The study was conducted in 20 adult patients with XLH who had previously participated in the phase 1 INT-001 or INT-002 studies of burosumab [68] .

Updated results from a phase II trial after 3-year (over 160 weeks) treatment of patients (aged 1-5 years) with X-linked hypophosphatemia demonstrated no new safety concerns. All patients had 1 treatment-emergent adverse event (TEAE). All TEAEs were mild (Grade 1) or moderate (Grade 2) except for one patient with a grade 3 TEAE (food allergy) and one with a grade 3 TEAE (increased serum amylase, 92% salivary/8% pancreatic). One patient had a serious TEAE (dental abscess leading to hospitalization). These grade 3 and serious TEAEs were considered unrelated to study drug. Previous results from a phase II trial after 24 week treatment of patients (n = 13, aged 1-4 years) with X-linked hypophosphatemia demonstrated adverse events consistent with the earlier findings. Injection-site reactions were observed in approximately 23% of patients, all of which were considered mild. No deaths or discontinuations were observed. Clinically meaningful changes were not observed in mean serum calcium, urinary calcium and in serum intact parathyroid hormone. No events of hyperphosphatemia and deaths or discontinuations were observed in the study. Tooth abscess, food allergy, injection site reactions, and hypersensitivity were the adverse events experienced by patients, which were unrelated to the study drug. The 64-week study will assess the safety, pharmacodynamics, and efficacy of burosumab administered every 2 weeks at a starting dose of 0.8mg/kg, which can be increased to 1.2mg/kg at any time during the trial [58] [107] [59] [60] .

No serious adverse events related to treatment, or calcification of renal or cardiac tissue, were observed in a phase I/II study of subcutaneous burosumab, at dosages of 0.05mg/kg to 0.6mg/kg once every four weeks (NCT01340482; INT-001). The most common adverse events associated with burosumab were nasopharyngitis, joint pain, diarrhoea, back pain, and restless legs syndrome. An injection site reaction caused one patient to discontinue treatment. No patient developed anti-burosumab antibodies. The open-label, multiple-dose phase I/II study enrolled 28 patients with X-linked hypophosphataemic rickets [72] [73] .

No serious adverse events occurred in a randomised, double-blind, placebo-controlled, single-dose phase I trial of burosumab in 38 adults with XLH. No patients developed anti-burosumab antibodies, and no safety concerns arose from ECGs, renal sonograms or biochemical analyses. In addition, there were discontinuations due to adverse events. A total of 6 patients reported adverse events; 4 in the IV dose group (24%) and 2 in the SC group (17%). IV doses ranged from 0.003 to 0.3mg/kg, and SC doses ranged from 0.1 to 1.0mg/kg [82] [83] .

In the UX023-CL201 and UX023-CL205 trials, in children with X-linked hypophosphataemia, all the adverse events (AEs) in the girls were mild or moderate in severity and most related-AEs were injection site reactions. None of the girls developed hyperphosphatemia. Burosumab administered every two weeks, led to a serious adverse even in one subject, in each study. The patient was hospitalized for fever/muscle pain that resolved within a day for CL201 and a dental abscess in CL205. Other adverse events were generally mild to moderate in severity and there were no clinically meaningful changes in serum or urine calcium or circulating parathyroid hormone levels. No subjects discontinued the study or developed hyperphosphataemia [105] [66] [60] .

Pharmacodynamics

Summary

In the phase III PIXLES trial, at both 64 weeks and 40 weeks, the mean serum phosphorus and renal phosphate reabsorption levels returned to normal compared with baseline post treatment with burosumab wherein mean serum phosphorus and renal phosphate reabsorption levels were below the lower limits of normal range in children treated with conventional therapy. Mean serum phosphorus levels post 40 weeks were 3.38 mg/dl and 2.55 mg/dl in burosumab and conventional therapy with mean change by 1.00 and 0.23 compared with baseline, respectively. At 40 weeks, least square mean change in serum phosphorus was 0.77 between both the arm (p < 0.0001). Significant differences were observed between treatment with crysvita and conventional therapy (p < 0.0001). Increase in serum 1,25 - dihydroxy vitamin D with maintained levels was observed in both the arms at week 40 as wells as at week 64 [52] [57] .

Initial data from an open-label, dose-finding phase II study of burosumab in patients with tumour-induced osteomalacia or epidermal nevus syndrome reveal that 6 of 8 treated patients achieved serum phosphorous levels after the treatment with burosumab began. An increase in the renal phosphate reabsorption (TmP/GFR) and serum 1,25 dihydroxy vitamin D levels was also observed in 7 out of 8 patients. One patient displayed no change in these markers [96] [94] .

In a randomised, double-blind phase I trial in 38 adults with XLH, single doses of either IV or SC burosumab increased serum phosphate levels compared to placebo for the higher doses (p<0.01). Peak serum phosphate effects occurred later with SC dosing (8 - 15 days) than with IV dosing (0.5 - 4 days). The duration of effect on serum phosphate was dose-related, was greater with SC than IV dosing, and persisted beyond 29 days with SC dosing. Increased renal re-absorption of phosphate and 1,25 dihydroxyvitamin D were seen. Serum calcium, serum parathyroid hormone, and urinary calcium excretion were minimally affected. IV doses ranged from 0.003 to 0.3 mg/kg, and SC doses ranged from 0.1 to 1.0 mg/kg [82] [83] .

Therapeutic Trials

Phase III

The results from the phase III trial showed that 89% (119/134) of patients completed 96 weeks of treatment and received 1 mg/kg burosumab. At Week 94, mean (±SE) baseline serum phosphorus was 1.98 (±0.03) mg/dL and was 2.97 (±0.05) mg/dL (midpoint of dose interval). At week 96, mean (±SE) iPTH level was 96 (±3.8) pg/mL at baseline and progressively declined to 79 (±3.3) pg/mL. Earlier, the data from the trial showed that after week 24, the overall mean serum phosphorus levels at the mid-point of the dose interval remained above the lower limit of normal in all the patienst in the study. Increase in serum 1,25(OH)2D were maintained. Substantial reductions from baseline were maintained in scores for stiffness (LS mean change +/- SE [95% CI]: -16.5 +/- 3.1 [-22.6, -10.4]), physical functioning (-8.7 +/- 2.0 [-12.7, -4.7]), and pain (-1.2 +/- 0.2 [-1.7, -0.8]). The trial met its primary endpoint of increasing serum phosphorus levels as 94% of patients treated with burosumab (n = 68) achieved serum phosphorus levels above the lower limit of normal and maintained levels in the low normal range through 24 weeks, compared to 8% in the placebo arm (n = 66; p < 0.0001). The trial also met its secondary endpoints. At week 24, stiffness improved by a mean score of 7.87 points for patients treated with burosumab compared to a 0.25 point worsening among patients in the placebo group (mean difference of 8.12; p = 0.0122). Physical function improved by 3.11 points for patients treated with burosumab compared to a 1.79 point worsening among patients in the placebo group (mean difference of 4.90 points; p=0.0478). A higher rate of complete healing of active fractures and pseudo-fractures, accompanied by a decline in the WOMAC stiffness score, as compared to placebo, was also observed at 24 weeks. Pain score improved by 0.79 for patients treated with burosumab compared to a 0.32 improvement among patients in the placebo group (mean score difference of 0.46 points; p = 0.0919). Results were directionally consistent towards improvement across all three key secondary endpoints. After pre-planned multiplicity adjustment, the improvement in stiffness among patients treated with burosumab remained statistically significant at the less than the 0.0167 threshold, while physical function and pain scores demonstrated strong trends. The study enrolled 134 patients, randomized 1:1 to burosumab at a dose of 1 mg/kg or placebo every four weeks for 24 weeks. Results from the 48-week treatment period showed that, 84% of patients who had received burosumab since the beginning of the study (n = 68) and 89% of patients who crossed over from placebo to burosumab after 24 weeks (n = 66), achieved and maintained serum phosphorus levels above the lower limit of normal (2.5 mg/dL). For patients treated with burosumab, stiffness further improved by 16.03 points at 48 weeks, and patients who crossed over from placebo to burosumab treatment had a mean change of 15.82 points from 24 to 48 weeks. Patients treated with burosumab had further improvements in pain scores by 1.09 points at 48 weeks while patients who crossed over from placebo to burosumab treatment had a mean change of 1.18 points from 24 to 48 weeks. Rate of fracture healing increased to 63% at 48 weeks compared with 43% at 24 weeks in patients treated with burosumab; in the crossover group the rate increased to 35% at week 48 [42] [43] [47] [41] [44] .

In a phase III trial in adult patients with X-Linked Hypophosphatemia (XLH), burosumab treatment resulted in increased healing of fractures compared with placebo. At the start of the study, 52% of patients (comprising 48% of patients randomised to burosumab and 56% of patients randomised to placebo) were having either active fractures (12%) or pseudofractures (47%) or both. At week 24, 37% of active fractures or pseudofractures in patients treated with burosumab were completely healed compared with 10% on placebo. At week 24, 3% of existing active fractures or pseudofractures treated with burosumab worsened compared to 11% on placebo. Updated results from six patients showed osteomalacia healing as evidenced by mean osteoid volume/bone volume decreases from 24.3% to 7%, lowering of osteoid thickness and a decrease in mineralisation lag time, representing a 71%improvement [31] [9] [49] [50] .

In updated results from the phase III PIXLES trial, post 64-week treatment with burosumab, the rickets scores were found to be superior when compared with conventional therapy, with a Least square (LS) mean treatment difference of +1.02 (p < 0.0001), in children with X-Linked hypophosphatemia (XLH) (n = 29) over conventional oral phosphate and active vitamin D therapy (n = 32). As assessed by the radiographic global impression of change (RGI-C) scale, significant improvement in rickets was observed in 86.2% of patients receiving burosumab compared with the 18.8% of patients who received conventional therapy (p = 0.0002). A greater reduction in the lower limb deformity was observed upon treatment with burosumanb compared with conventional treatment therapy with a LS mean treatment difference of +0.97 (p < 0.0001). The Rickets Severity Scores (RSS) improvement was observed to be more with burosumab treatment than the conventional treatment (LS mean treatment difference of -1.21, p < 0.0001). Consistent with the 40 week treatment observation, the mean serum alkaline phosphatase levels decreased and returned to the normal range in patients treated with burosumab, compared to patients who received conventional treatment (p < 0.0001). A significant increase in the growth (increase in standing height/recumbent length z-score) and walking ability (measured by the six-minute walk test (6MWT)) was observed in patients who received burosumab, with a LS mean treatment difference +0.14 (p = 0.0490) and +45.6 meters (p = 0.0399), respectively, compared with patients treated with conventional therapy. Earlier, at 40 weeks, post treatment with burosumab, the trial met its primary end points in which burosumab demonstrated superior efficacy in improving rickets in children with XLH (n=29) over conventional oral phosphate and active vitamin D therapy (n=32). After 40 weeks treatment, 72% patients showed substantial healing of rickets on RGI-C scale compared with 6% of patients receiving conventional therapy. Least square mean in burosumab arm was +1.92 vs. +0.77 in conventional therapy arm with difference of +1.14 (95% CI, 0.83, 1.45; p < 0.0001). Burosumab showed a 2.8 fold improvement in rickets compared with patients receiving conventional therapy on RSS scale with Least square mean change from baseline of -1.34 (95% CI, -1.74, -0.94; p < 0.0001). Burosumab also improved growth (height z-score and growth velocity) and six-minute walk test compared with conventional therapy, however difference was not statistically significant. At week 64, the improvement in the least square (LS) mean (LS mean [±SE; 95%CI]) RGI-C Global Score for rickets was greater on burosumab (+2.06 [0.072; 1.92, 2.20]) compared with either higher-dose (+1.02 [0.241; 0.55, 1.50]) or lower-dose (+1.04 [0.162; 0.73, 1.36]) Pi. The mean decrease in the total RSS from baseline was also greater on burosumab (-2.23 [0.117; -2.46, -2.00]), compared with higher-dose (-0.87 [0.264; -1.39, -0.35] or lower-dose (-1.09 [0.180; -1.45, -0.74]) oral phosphate. Similarly, the mean RGI-C Lower Limb Deformity Score was greater on burosumab (+1.25 [0.170; 0.92, 1.59]) compared with either higher-dose (+0.32 [0.188; -0.05, 0.69]) or lower-dose (+0.26 [0.146; -0.02, 0.55]) oral phosphate [51] [52] [53] [57] .

Phase II:

Updated results from 17 patients at week 144 showed bone scan at BL, 68 (27%) and 81 (33%) were fully healed at W96 and W144, respectively; 56 (23%) and 32 (13%) were partially healed at W96 and W144, respectively. Mean (SD) Global Fatigue Score decreased from 5.6 (2.5) at BL to 3.5 (3.0) at W48, and to 3.8 (2.2) at W144 (both p<0.01). All 3 domains of the Brief Pain Inventory decreased with burosumab (W144 Pain Severity and Pain Interference p<0.05), indicating reduced pain. The SF-36 mean (SD) physical component summary score increased from 33 (10) at BL to 39 (10) at W48 (p<0.05) and to 41 (12) at W144 (p<0.01), indicating improved physical functioning. The mean (SD) number of sit-to-stand repetitions, an assessment of proximal muscle function, increased from 6.7 (4.2) at BL to 8.5 (4.2) at W48 (n=10; p<0.01) [100] . According to updated interim results from 17 patients in a phase II study of burosumab in tumour-induced osteomalacia or epidermal nevus, mean serum phosphorus, renal phosphate reabsorption (TmP/GFR) and serum 1,25 dihydroxy vitamin D levels increased over 24 weeks of treatment. The mean serum phosphorus level was 1.6 mg/dL prior to burosumab treatment, and after washout with oral phosphate treatment, which was below lower limit of normal of 2.5mg/dL. The mean serum phosphorus level was normal within one week of treatment, and was maintained in the low normal range from week 10 to week 24 of treatment. Improvement in serum phosphorus and other bone mineral metabolism measures was consistent with those observed in studies of burosumab in paediatric and adult patients with X-linked hypophosphataemia (XLH). Improved bone mineral density at 24 weeks of treatment was shown by six out of seven responding patients. At week 24 there was a statistically significant increase in mean percent change from baseline levels (51% and 38% respectively) in bone turnover markers, Procollagen type 1 N-terminal propeptide (P1NP) and C-telopeptide of type I collagen (CTX-1). Burosumab also demonstrated a statistically significant increase in lower limb strength as seen with the increase in repetitions at 24 weeks in the Sit-to-Stand test (p < 0.01). An improvement from severe osteomalacia at baseline, to mild osteomalacia at 48 weeks, was shown by one patient and the patient had previously shown resolution of four fractures at 24 weeks of treatment. For the same patient, there was an improvement in bone mineral density by 2% and 3%, in the lumber spine and total hip, respectively. Earlier, interim results from the trial showed an increase in mean serum phosphate from 1.7 (0.2) mg/dL at baseline to 2.9 (0.56) mg/dL within 1 week of treatment which was accompanied by an increased mean TmP/GFR and serum 1,25(OH)2D values in all but one patient who had metastatic sarcoma. Improvement in skeletal manifestations was evident in the two patients with data up to week-24. Patient one had a Tc99 bone scan with areas of increased uptake in the ribs/tibia consistent with multiple fractures/pseudofractures. By week-24, uptake was normal at the four rib sites, with no new regions of increased uptake. Patient two had a Tc99 bone scan consistent with fractures/pseudo-fractures in the clavicle, humerus, and tibia that was not resolved by week-24 but with no new regions of increased uptake. Lumbar spine and total hip BMD increased by 21% and 6%, respectively, in the same patient over 24-weeks [9] [107] [95] [97] [96] [94] . Updated results from 48-week treatment period showed that all 10 patients with evaluable paired bone biopsies demonstrated significant improvements (57%) from baseline in mean osteoid volume/bone volume (mean decrease from 26.1% to 11.2%). The patients also showed mean improvements of 32% and 26% in osteoid thickness and osteoid surface/bone surface parameters respectively. These patients also experienced a meaningful improvement in mineralisation lag time [106] . Updated 48 week and 72 week data indicated that burosumab increased serum phosphorus and serum 1,25 dihydroxy vitamin D levels, demonstrated improvements in osteomalacia, mobility and vitality, and reduction in fatigue [36] . Histomorphometric indices were improved at week 48, demonstrated by mean percentage changes in osteoid thickness (37%), osteoid volume/bone volume (40%), osteoid surface/bone surface (-5%), and mineralization lag time (median percentage change -78%). Increase in mean (SD) vitality score from 41 (14) to 47 (12) at week 48 (P = 0.075) and to 49 (12) at week 72 (P = 0.012) was observed. There was an increase in SF-36 mean (SD) physical component summary score from 34 (11) at baseline to 39 (10) at week 48 (P = 0.059) and to 42 (10) at week 72 (P = 0.003). Mean (SD) Global Fatigue Score decreased from 5.3 (2.8) at baseline to 3.6 (2.9) at week 48 (P = 0.020) and to 3.3 (2.7) at week 72 (P = 0.004). There was an increase in mean (SD) number of sit-to-stand repetitions from 6.9 (4.0) at baseline to 8.6 (4.2) at week 48 (n=10; P = 0.004) [98] [87] [99] .

In a phase II trial of burosumab in tumour-induced osteomalacia or epidermal nevus patients (n=13), 69% of patients achieved normal phosphate levels through week 24 and maintained normal or near normal phosphate levels through week 88 [99] [87] [101] .

Updated results from the phase II CL201 trial in patients with X-linked hypophosphatemia (n=52) demonstrated that burosumab treatment showed sustained improvements in phosphate metabolism, resolving rickets better physical functioning, and less pain. The patients also showed continued improvement in leg deformities and growth. Out of 52, 11 girls developed fused growth plates at the distal femur and proximal tibia (mean age: baseline 9.8 years, week 160 13.3 years; mean Tanner stage: baseline 1.5, week 160 3.4). Serum phosphorus levels for these 11 girls were maintained near the lower limit of normal (3.2 mg/dL) throughout the study. For the 10/11 girls whose last visit with open growth plates was week 88, the mean total Rickets Severity Score (RSS) decreased from 2.1 at baseline to 0.4 at week 88, and the mean week 88 Radiographic Global Impression of Change (RGI-C) was +2.3, both indicating improved rickets. For the 1 girl whose last visit with open growth plates was week 64, RSS decreased to 0 from 1.5 at baseline, with a week 64 RGI-C of +2.7. In these 11 girls, the LS mean RGI-C lower limb deformity score improved: +0.4 at week 64 and +1.1 at week 160. Standing height Z-score improved from -1.7 at baseline to -1.5 at week 160. At week 160, nephrocalcinosis scores were unchanged from baseline in 10/11 girls and 1-point lower in 1 girl. Mean subject-reported sports/physical functioning and pain/comfort scores were normal [69] . Earlier results showed that treatment with burosumab was associated with sustained renal phosphate reabsorption (TmP/GFR) and serum 1,25 dihydroxy vitamin D levels through 64 weeks of treatment. A statistically significant improvement in rickets scores was observed in all groups at 64 weeks, with the greatest improvements in patients with higher baseline rickets scores (RSS = 1.5) who received bi-weekly dosing of burosumab. A 51% reduction in RSS score (p < 0.0001) was observed in all patients (n = 52). Higher baseline rickets scores (n = 34) was associated with 59% reduction in RSS score (p < 0.0001). Patients who were dosed bi-weekly (n = 26) had a 58% reduction in RSS score (p < 0.0001). Patients with higher baseline rickets scores, dosed bi-weekly (n = 17) had a 62% reduction in RSS score (p < 0.0001). All patients experienced (n = 52) a significant improvement of +1.57 (p < 0.0001) in RGI-C score (severity of rickets) at 64 weeks; a mean improvement of +1.98 (p < 0.0001) was experienced by patients with higher baseline rickets scores (n=34) while 77% (26/34) within the higher severity subset experienced substantial healing (score >2). Bi-weekly dosed patients experienced (n=26) a mean improvement in RGI-C score of +1.62 (p < 0.0001). Patients with higher baseline rickets scores who were dose bi-weekly (n=17) showed a mean improvement of +2.08 (p < 0.0001) and 82% experienced substantial healing. Patients with higher baseline rickets scores showed more growth impairment (baseline height percentile = 5.84), and these patients demonstrated greater improvement in growth. Among all patients (n = 52), growth velocity improved by a mean of +0.55 cm/year (p = 0.0376), and there was 0.15 change in height z-score (p < 0.0001). Patients with higher baseline rickets scores had a +0.86 cm/year improvement in growth velocity (p = 0.0175) and a 0.17 change in height z-score (p = 0.0016). Patients who were dosed bi-weekly (n=26) experienced a +0.73 cm/year change in growth velocity (p=0.0160) and a 0.18 change in height z-score (p = 0.0002). Patients with higher baseline rickets scores who were dosed bi-weekly (n = 17) had a +1.11 cm/year change in growth velocity (p=0.0076) and a 0.18 change in height z-score (p = 0.0063). Patients with walking impairment at baseline (defined by < 80% predicted normal walk distance in 6MWT) in the bi-weekly dosing group (n = 14) achieved a mean increase of 85 meters (p < 0.0001). When evaluating the Global score of all five domains in those patients with substantial impairment at baseline (n = 28), defined as baseline scores < 40 or one standard deviation below the normalized score of 50), a mean improvement of +14.1 (p < 0.0001) was observed. Serum alkaline phosphatase decreased by mean of 98 (76) U/L (P < 0.0001). The randomised, open-label, dose-finding study enrolled 52 patients between five and 12 years old, 49 of whom received therapy (oral phosphate/active vitamin D therapy) for an average of approximately seven years prior to entering the study [59] [68] [24] [61] [25] [67] [66] .

Over four months, all patients showed an increase in serum phosphorous values, 89% of which were at the low end of the normal range, following repeat once-monthly doses of burosumab, at subcutaneous dosages of 0.05 mg/kg to 0.6 mg/kg, in a phase I/II trial (NCT01340482; INT-001). After the fourth dose, the peak mean serum phosphorus values increased approximately 60% from mean baseline value of 1.89 ± 0.33 mg/dL to 3.03 ± 0.42 mg/dL. Similar increases in mean reabsorption of phosphate from the urine (TmP/GFR) and mean serum calcitriol levels were also observed. Evaluation of bone remodelling markers showed significant increases in procollagen type I N propeptide (p < 0.05) after all doses and osteocalcin (p < 0.05) after the fourth dose, measured from baseline. There was also a statistically significant improvement in physical health, bodily pain, and physical component summary scales measured through Medical Outcomes Study 36-item Short Form, Version 2 (SF-36v2) questionnaire. There was also a statistically significant increase in physical functioning and stiffness scales measured through Western Ontario and McMaster University Osteoarthritics Index (WOMAC) questionnaire. There were no significant changes in levels of parathyroid hormone, serum calcium, or urinary calcium excretion. The open-label, multiple-dose phase I/II study enrolled 28 patients with X-linked hypophosphataemic rickets. Increases in serum phosphorous levels, serum calcitriol levels and urinary phosphorous reabsorption were sustained over a 12 month extension period, in a phase I/II study in 22 patients from INT-001 study who received additional 12 doses of burosumab (NCT01340482; INT-002). Serum phosphorous reached normal levels (2.5 to 4.5 mg/dL) in 52.6% to 85.7% of patients at peak time on days 7 and 14 following each dose. Increases in bone remodelling markers was also sustained during the extension study [76] [77] [72] [73] .

In the phase II adult extension study, treatment with burosumab resulted in increased serum phosphate levels, renal phosphate reabsorption and serum 1,25 dihydroxy vitamin D at 24 weeks of treatment. A significant reduction in the Brief Pain Inventory Question 3 (BPI-Q3) score from baseline was observed (p=0.0268; 1.1 point reduction from 6.6 at baseline to 5.5 at 24 weeks). A significant change was reported in BPI pain interference (p=0.0009) and pain severity (p=0.0141) scores and also in WOMAC pain, stiffness and physical function domain scores. Mean patient TUG scores improved by 2 seconds (p=0.04) at week 24. The mean increase in distance walked of 25 meters (p=0.05) from baseline was reported. The study was conducted in 20 adult patients with XLH who had previously participated in the phase 1 INT-001 or INT-002 studies of burosumab [68] .

Updated results from a phase II trial after 3-year (over 160 weeks) treatment of patients (aged 1-5 years) with X-linked hypophosphatemia demonstrated that burosumab rapidly restored Pi homeostasis, improved rickets, and normalized serum ALP. Burosumab rapidly corrected fasting serum Pi with mean (SD) levels of 2.5 (0.3) mg/dL at baseline, 3.7 (0.5) mg/dL at Week 1 (W1), 3.4 (0.5) mg/dL at W64, and 3.4 (0.5) mg/dL at W160 (normal range: 3.2-6.1 mg/dL). Lower Rickets Severity Score (RSS) indicated improved rickets. Total RSS decreased from 2.9 (1.4) at Baseline to 1.2 (0.5) at W40 and to 0.9 (0.5) at W64 and was maintained through W160 [1.0 (0.6)]. Positive Radiographic Global Impression of Change (RGI-C) scores indicate healing rickets relative to baseline. Global RGI-C scores indicating substantial healing (≥+2) at W40 [+2.2 (0.3)] and W64 [+2.2 (0.4)] were maintained through W160 [+2.2 (0.4)]. Similarly, lower limb deformity RGI-C scores were +1.2 (0.6) at W40 and +1.5 (0.5) at W64, and sustained healing was evident at W160 [+2.0 (0.3)]. Wrist and knee RSSs and RGI-C scores similarly improved. The upper limit of normal for serum ALP ranged from 297 to 345 U/L depending on the child’s age and sex. Mean ALP was 549 (194) U/L at Baseline, normalized by W40 [335 (88) U/L], and was sustained through W160 [302 (71) U/L]. Previous results from a phase II trial after 24 week treatment of patients (n = 13, aged 1-4 years) with X-linked Hypophosphatemia demonstrated increased mean serum phosphorus, and maintained levels in the low normal range through 24 and 40 weeks of treatment. Burosumab increased mean serum phosphorus levels by 1.2 mg/dL into the low normal range after one week of treatment and these levels were maintained through week 40 with 77% of children achieving normal serum phosphorus levels at week 40. Serum 1,25 dihydroxy vitamin D levels were also increased from baseline to week 40 of treatment. Patients also demonstrated increases in serum 1,25 dihydroxy vitamin D levels, and significant decreases in alkaline phosphatase levels (-39%, p < 0.0001). Mean total RSS score was improved significantly (59% reduction) at week 40 (p < 0.0001). The change in rickets severity was also assessed at week 40 by the RGI-C score which demonstrated substantial healing (RGIC score > 2) in all patients (p < 0.0001). Burosumab treatment also resulted in significantly improved bowing as determined by RGI-C lower limb deformity (p < 0.0001). Serum alkaline phosphatase activity was lowered. The 64-week study will assess the safety, pharmacodynamics, and efficacy of burosumab administered every 2 weeks at a starting dose of 0.8mg/kg, which can be increased to 1.2mg/kg at any time during the trial [58] [107] [59] [60] .

Results from the UX023-CL201 and UX023-CL205 trials, in children with X-linked hypophosphataemia, burosumab administered every two weeks significantly improved phosphate homeostasis and rickets. At week 40, Total Thacher Rickets Severity Score (RSS) was reduced by 61% and 59% in CL201 and CL205, respectively (both p < 0.0001). Rickets as assessed by RGI-C at week 40 was improved, as well (CL201: +1.72 ± 0.12, p < 0.0001; CL205: +2.33 ± 0.08, p < 0.0001). Mean (SD) dose at week 40 was 0.98 mg/kg and 0.89 mg/kg for CL201 and CL205, respectively. Mean (SD) serum phosphorus increased from 2.4 mg/dL at baseline to 3.3 mg/dL at week 40 in CL201 (p < 0.0001); and from 2.5 mg/dL at baseline to 3.5 mg/dL at week 40 in CL205 (p < 0.0001). Mean alkaline phosphatase decreased 17% from 462 U/L at baseline to 383 U/L at week 40 in CL201 (p = 0.0003); and 39% from 549 U/L at baseline to 335 U/L at week 40 in CL205 (p < 0.0001) [105] [66] [60] .

Future Events

Expected Date Event Type Description Updated
31 Dec 2020 Regulatory Status Kyowa Kirin anticipates the final decision of EMA for burosumab in X-linked dominant hypophosphataemic rickets (In adults) in the second half of 2020 [26] 06 Oct 2020
30 Jun 2020 Regulatory Status Ultragenyx Pharmaceutical announces intention to submit sBLA for Osteomalacia (Tumour-induced) to the US FDA in the first half of 2020 [90] 20 Feb 2020
31 Dec 2019 Regulatory Status Ultragenyx expects approval of burosumab for X-linked dominant hypophosphataemic rickets in Columbia (SC), in 2019 (9253560) [35] 29 Mar 2019
31 Mar 2019 Regulatory Status Ultragenyx Pharmaceutical expects to launch burosumab for X-linked dominant hypophosphataemic rickets (In adolescents, In adults, In children, In infants) in Canada in early 2019 [31] 30 Oct 2020
30 Jun 2018 Regulatory Status Kyowa Hakko Kirin and Ultragenyx Pharmaceutical intend to launch burosumab (Crysvita®) in Germany in 2Q 2018 [17] 27 Feb 2018
17 Apr 2018 Regulatory Status FDA assigns PDUFA action date of 17/04/2018 for burosumab for X-linked dominant hypophosphataemic rickets (In children, In infants, In adults) [7] 23 May 2018
23 Feb 2018 Regulatory Status Final decision on the grant of conditional marketing authorisation by the EMA for burosumab for the treatment of X-linked hypophosphataemia (XLH) in children 1 year of age and older, and adolescents is expected in Q1 2018 [19] 27 Feb 2018
30 Jul 2017 Regulatory Status Ultragenyx announces intention to submit BLA for paediatric and adult X-linked hypophosphataemia to the USFDA in the second half of 2017 [22] 29 Aug 2017
30 Jun 2017 Trial Update Kyowa Hakko Kirin Pharma plans a phase III trial for X-linked dominant hypophosphataemic rickets and Osteomalacia (In infants, In children) in Japan (JapicCTI-173614) (NCT03233126) 17 Aug 2017

Development History

Event Date Update Type Comment
07 Sep 2021 Phase Change - Registered Registered for Osteomalacia (In adults) in Canada (SC) [91] Updated 09 Sep 2021
06 Aug 2021 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets in Singapore (SC) prior to August 2021 (Kyowa Hakko Kirin pipeline, August 2021) Updated 06 Aug 2021
06 Aug 2021 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets in South Africa (SC) prior to August 2021 (Kyowa Hakko Kirin pipeline, August 2021) Updated 06 Aug 2021
21 Jul 2021 Regulatory Status European Medicines Agency approves burosumab for the treatment of X-Linked hypophosphataemic rickets (In children, In infants, In adolescents) (option of self administration) in European Union, Liechtenstein, Norway and Iceland (SC, Injection) [14] Updated 21 Jul 2021
10 May 2021 Regulatory Status CHMP recommends approval of burosumab for X-Linked hypophosphataemic rickets (In children, In infants, In adolescents) (option of self administration) in European Union (SC, Injection) [15] Updated 12 May 2021
31 Mar 2021 Phase Change - Preregistration Preregistration for Osteomalacia in European Union (SC) prior to March 2021 [28] Updated 10 May 2021
31 Mar 2021 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets (In children, In infants) in Australia (SC) [28] Updated 10 May 2021
31 Mar 2021 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets in Singapore, South Africa (SC) prior to March 2021 [28] Updated 10 May 2021
20 Mar 2021 Scientific Update Updated efficacy and adverse events data from a phase II trial in X-linked dominant hypophosphataemic rickets presented at the 103rd Annual Meeting of the Endocrine Society (ENDO-2021) [58] Updated 11 May 2021
02 Feb 2021 Phase Change - Marketed Launched for X-linked dominant hypophosphataemic rickets (In children, In infants) in United Kingdom (SC) Updated 12 May 2021
01 Feb 2021 Financial Update Credit Suisse financial data update Updated 14 Mar 2021
31 Dec 2020 Phase Change - Preregistration Preregistration for Osteomalacia in Canada (SC) prior to December 2020 [28] Updated 10 May 2021
31 Dec 2020 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets in Bahrain (SC) prior to December 2020 [28] Updated 10 May 2021
31 Dec 2020 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets in Malaysia, Thailand (SC) prior to December 2020 [28] Updated 10 May 2021
31 Dec 2020 Phase Change - Registered Registered for Osteomalacia in China (SC) prior to December 2020 [28] Updated 10 May 2021
31 Dec 2020 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets in Bahrain (SC) prior to December 2020 [28] Updated 10 May 2021
31 Dec 2020 Patent Information Ultragenyx Pharmaceutical has rights to several granted and pending patents in the US and outside US, covering burosumab [104] Updated 10 Mar 2021
27 Oct 2020 Phase Change - Marketed Launched for Osteomalacia (In adolescents, In children, In adults) in USA (SC) before October 2020 [86] Updated 30 Oct 2020
02 Oct 2020 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets (In adults) in European Union, Iceland, Norway, Liechtenstein (SC) [16] Updated 06 Oct 2020
25 Aug 2020 Phase Change - Marketed Launched for X-linked dominant hypophosphataemic rickets in Greece (SC) Updated 12 May 2021
30 Jul 2020 Regulatory Status Kyowa Kirin anticipates the final decision of EMA for burosumab in X-linked dominant hypophosphataemic rickets (In adults) in the second half of 2020 [26] Updated 06 Oct 2020
27 Jul 2020 Regulatory Status CHMP recommends the extended approval for burosumab in X-linked dominant hypophosphataemic rickets (In adults) in European Union [27] Updated 28 Jul 2020
30 Jun 2020 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets in China, Hong Kong, Oman (SC) before June 2020 (Kyowa Kirin's pipeline, August 2020) Updated 10 Aug 2020
18 Jun 2020 Phase Change - Registered Registered for Osteomalacia (In children, In adolescents, In adults) in USA (SC) [87] Updated 22 Jun 2020
18 Jun 2020 Scientific Update Efficacy data from a phase II trial in Osteomalacia released by Ultragenyx and Kyowa Kirin [87] [99] (NCT02722798) Updated 22 Jun 2020
18 Jun 2020 Scientific Update Updated efficacy and safety data from a phase II trial in Osteomalacia released by Ultragenyx and Kyowa Kirin [87] [99] (NCT02304367) Updated 22 Jun 2020
06 May 2020 Regulatory Status FDA assigns PDUFA action date of 18/06/2020 for burosumab for Osteomalacia in USA (SC) (tumour induced) [88] Updated 09 May 2020
28 Mar 2020 Scientific Update Efficacy and adverse event data from a phase III trial in X-linked dominant hypophosphataemic rickets presented at the 102nd Annual Meeting of the Endocrine Society (ENDO-2020) [42] Updated 08 Jul 2020
28 Mar 2020 Scientific Update Efficacy and safety data from a phase II trial in Osteomalacia presented at the 102nd Annual Meeting of the Endocrine Society (ENDO-2020) [100] Updated 07 Jul 2020
28 Mar 2020 Scientific Update Updated efficacy and adverse events data from the phase III PIXLES trial in X-linked dominant hypophosphataemic rickets presented at the 102nd Annual Meeting of the Endocrine Society (ENDO-2020) [51] Updated 07 Jul 2020
25 Feb 2020 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets (In children, In infants, In adults) in Switzerland (SC) [29] Updated 27 Feb 2020
25 Feb 2020 Regulatory Status Kyowa Kirin plans to launch Burosumab in Switzerland [29] Updated 27 Feb 2020
12 Feb 2020 Regulatory Status Burosuma will be assessed within the ultra-orphan pathway for X-linked hypophosphataemia in Scotland [30] Updated 21 Feb 2020
12 Feb 2020 Regulatory Status Ultragenyx plans to launch burosuma for X-linked hypophosphataemia in Scotland [30] Updated 21 Feb 2020
10 Feb 2020 Phase Change - Marketed Launched for X-linked dominant hypophosphataemic rickets (In infants, In neonates, In adults, In adolescents) in France (SC) Updated 12 May 2021
31 Dec 2019 Phase Change - Preregistration Preregistration for Osteomalacia in South Korea, China (SC), as at December 2019 [13] Updated 20 Feb 2020
31 Dec 2019 Phase Change - Preregistration Preregistration for Osteomalacia in USA (SC) [13] Updated 20 Feb 2020
31 Dec 2019 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets in South Korea, China (SC), as at December 2019 [13] Updated 20 Feb 2020
18 Dec 2019 Phase Change - I/II Phase-I/II clinical trials in X-linked dominant hypophosphataemic rickets (In infants, In neonates) in France (SC) (EudraCT2019-000469-19) Updated 27 Mar 2020
18 Dec 2019 Licensing Status Ultragenyx Pharmaceutical entered into licensing agreement with Royalty Pharma [2] Updated 23 Dec 2019
18 Dec 2019 Phase Change - I/II Phase-I/II clinical trials in X-linked dominant hypophosphataemic rickets (In infants, In neonates) in Austria, Germany, before December 2019 (SC) (EudraCT2019-000469-19) Updated 18 Dec 2019
06 Dec 2019 Trial Update Ultragenyx Pharmaceutical completes a phase II trial in X-linked dominant hypophosphataemic rickets (In adolescents, In adults, In children, In infants, In neonates) in USA (SC) (NCT03581591) Updated 28 Jan 2020
30 Nov 2019 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets (In adults) in European Union (SC), before November 2019 [13] Updated 20 Feb 2020
30 Nov 2019 Regulatory Status European Medicines Agency accepts application for Burosumab for X-linked dominant hypophosphataemic rickets (In adults) in European Union for review [13] Updated 20 Feb 2020
31 Oct 2019 Phase Change - I/II Phase-I/II clinical trials in X-linked dominant hypophosphataemic rickets (In infants, In neonates) in Sweden (SC) (EudraCT2019-000469-19) Updated 14 Nov 2019
30 Sep 2019 Regulatory Status The US FDA approved burosumab for X-linked dominant hypophosphataemic rickets in infants of age six months and above in USA [5] Updated 07 Oct 2019
20 Sep 2019 Scientific Update Efficacy data from the phase II CL201 trial in X-linked dominant hypophosphataemic rickets presented at the 41st Annual Meeting of the American Society for Bone and Mineral Research Session (ASBMR-2019) [69] Updated 11 Feb 2020
20 Sep 2019 Scientific Update Final efficacy and adverse events data from a phase III trial in X-linked Hypophosphatemia presented at the 41st Annual Meeting of the American Society for Bone and Mineral Research (ASBMR-2019) [43] Updated 11 Feb 2020
20 Sep 2019 Phase Change - Registered Registered for Osteomalacia in Japan (SC) [33] Updated 25 Sep 2019
20 Sep 2019 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets (In adults) in Japan (SC) [33] Updated 25 Sep 2019
20 Sep 2019 Regulatory Status Burosumab receives Orphan Drug status for X-linked dominant hypophosphataemic rickets in Japan before September 2019 [33] Updated 25 Sep 2019
20 Sep 2019 Regulatory Status Burosumab receives Orphan Drug status for Osteomalacia in Japan before September 2019 [33] Updated 25 Sep 2019
10 Sep 2019 Regulatory Status Ultragenyx Pharmaceutical announces intention to submit sBLA for Osteomalacia (Tumour-induced) to the US FDA in the first half of 2020 [90] Updated 20 Feb 2020
10 Sep 2019 Trial Update Ultragenyx Pharmaceutical completes a phase II trial in X-linked dominant hypophosphataemic rickets (In children, In infants) in USA (SC) (NCT02750618) Updated 18 Oct 2019
10 Sep 2019 Regulatory Status Ultragenyx Pharmaceutical completes pre-sBLA meeting with the FDA to discuss sBLA submission for Osteomalacia (Tumour-indced) [90] Updated 12 Sep 2019
15 Jul 2019 Trial Update Ultragenyx Pharmaceutical and Kyowa Hakko Kirin Pharma completes a phase III trial in X-linked dominant hypophosphataemic rickets (In children, In infants) in South Korea, USA, Australia, Canada, Germany, Denmark, Ireland, Japan, Spain, United Kingdom, Italy and Sweden (NCT02915705) Updated 07 Aug 2019
01 Jul 2019 Company Involvement Kyowa Hakko Kirin is now called Kyowa Kirin Updated 16 Jul 2019
31 Mar 2019 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets in Kuwait, Taiwan, Switzerland (SC) before March 2019 (Kyowa Hakko Kirin pipeline, July 2019) Updated 10 Jul 2019
31 Mar 2019 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets in Israel (SC) before March 2019 (Kyowa Hakko Kirin pipeline, July 2019) Updated 10 Jul 2019
31 Mar 2019 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets in United Arab Emirates (SC) before March 2019 (Kyowa Hakko Kirin pipeline, July 2019) Updated 10 Jul 2019
26 Mar 2019 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets (In adolescents, In adults, In children, In infants) in Brazil (SC) [35] Updated 29 Mar 2019
26 Mar 2019 Regulatory Status Ultragenyx expects approval of burosumab for X-linked dominant hypophosphataemic rickets in Columbia (SC), in 2019 [36] [35] Updated 29 Mar 2019
23 Mar 2019 Scientific Update Additional adverse events data from the phase III PIXLES trial in X-linked dominant hypophosphataemic rickets presented at the 101st Annual Meeting of the Endocrine Society (ENDO-2019) [56] Updated 07 May 2019
23 Mar 2019 Scientific Update Adverse events efficacy data from a Updated efficacy data from a phase II trial in Osteomalacia presented at the 101st Annual Meeting of the Endocrine Society (ENDO-2019) [98] Updated 07 May 2019
01 Mar 2019 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets in Israel (SC) before March 2019 (Kyowa Hakko Kirin pipeline, July 2019) Updated 10 Jul 2019
01 Mar 2019 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets in United Arab Emirates (SC) before March 2019 (Kyowa Hakko Kirin pipeline, July 2019) Updated 10 Jul 2019
19 Feb 2019 Phase Change - Marketed Launched for X-linked dominant hypophosphataemic rickets (In adolescents, In children) in Turkey (SC) before February 2019 Updated 26 Feb 2019
19 Feb 2019 Phase Change - Marketed Launched for X-linked dominant hypophosphataemic rickets (In adolescents, In children, In infants, In adults) in Canada (SC) before February 2019 Updated 26 Feb 2019
15 Feb 2019 Scientific Update Efficacy, pharmacodynamics and adverse events data from the phase-III PIXLES trial in X-linked dominant hypophosphataemic rickets (In infants, In children) released by Ultragenyx and Kyowa Kirin (SC) [52] Updated 18 Feb 2019
07 Jan 2019 Phase Change - Marketed Launched for X-linked dominant hypophosphataemic rickets (In children, In adolescents) in Netherlands, Poland (SC) Updated 25 Sep 2019
07 Jan 2019 Phase Change - Preregistration Preregistration for Osteomalacia in Japan (SC) [34] Updated 11 Jan 2019
07 Jan 2019 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets (In adults) in Japan (SC) [34] Updated 11 Jan 2019
06 Dec 2018 Regulatory Status Ultragenyx Pharmaceutical expects to launch burosumab for X-linked dominant hypophosphataemic rickets (In adolescents, In adults, In children, In infants) in Canada in early 2019 [31] Updated 30 Oct 2020
06 Dec 2018 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets (In adolescents, In children, In infants, In adults) in Canada (SC) [31] Updated 12 Dec 2018
04 Dec 2018 Trial Update Ultragenyx Pharmaceutical completes a phase III trial in X-linked dominant hypophosphataemic rickets (In adults) in USA, Canada, Denmark, France, Japan, and South Korea (NCT02537431) Updated 15 Jan 2019
05 Nov 2018 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets in Colombia and Brazil (SC) prior to November 2018 [36] Updated 13 Nov 2018
05 Nov 2018 Scientific Update Updated efficacy and adverse events data from a phase II trial in Osteomalacia presented at the 40th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR-2018) [36] Updated 13 Nov 2018
30 Oct 2018 Trial Update Ultragenix completes a phase II trial in X-linked dominant hypophosphataemic rickets (In children) in the USA, United Kingdom, France, Netherlands (NCT02163577) Updated 27 Nov 2018
09 Oct 2018 Trial Update Kyowa Hakko Kirin initiates a phase III trial for X-linked dominant hypophosphataemic rickets (In adults) in France (SC) (EudraCT2018-000202-37) Updated 03 Apr 2019
28 Sep 2018 Trial Update Ultragenyx Pharmaceutical and Kyowa Hakko Kirin completes a phase IIb trial in X-linked dominant hypophosphataemic rickets in USA (SC) (NCT02312687) Updated 07 Jan 2019
05 Sep 2018 Trial Update Kyowa Hakko Kirin initiates an expanded-access programme for X-linked hypophosphataemia in United Kingdom [38] Updated 06 Sep 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
17 May 2018 Scientific Update Efficacy and adverse events data from the phase III PIXLES trial in X-linked dominant hypophosphataemic rickets released by Ultragenyx Pharmaceutical [53] (NCT02915705) Updated 23 May 2018
01 May 2018 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets (In children, In infants, In adolescents, In adults) in Canada (SC) [32] Updated 13 Aug 2018
27 Apr 2018 Phase Change - Marketed Launched for X-linked dominant hypophosphataemic rickets (In children, In adolescents, In infants, In adults) in USA (SC) [6] Updated 04 May 2018
17 Apr 2018 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets (In children, In infants, In adults) in USA (SC) [12] Updated 18 Apr 2018
17 Mar 2018 Scientific Update Safety and adverse events data from the phase II UX023-CL201 and UX023-CL205 study presented at the Annual Meeting of the Endocrine Society [105] Updated 24 Apr 2018
23 Feb 2018 Phase Change - Registered Registered for X-linked dominant hypophosphataemic rickets (In children, In adolescents) in European Union, Norway, Iceland, Liechtenstein (SC) - First global approval [17] Updated 27 Feb 2018
23 Feb 2018 Regulatory Status Kyowa Hakko Kirin and Ultragenyx Pharmaceutical intend to launch burosumab (Crysvita®) in Germany in 2Q 2018 [17] Updated 27 Feb 2018
20 Feb 2018 Scientific Update Updated efficacy data from a phase II trial in Osteomalacia released by Ultragenyx Pharmaceutical [106] (NCT02304367) Updated 22 Feb 2018
31 Jan 2018 Phase Change - III Phase-III clinical trials in X-linked dominant hypophosphataemic rickets (In neonates, In adolescents, In children, In infants) in USA (SC) (NCT03581591) Updated 28 Jan 2020
22 Dec 2017 Phase Change - Discontinued(I) Discontinued - Phase-I for X-linked dominant hypophosphataemic rickets in USA (IV) Updated 22 Dec 2017
15 Dec 2017 Regulatory Status Final decision on the grant of conditional marketing authorisation by the EMA for burosumab for the treatment of X-linked hypophosphataemia (XLH) in children 1 year of age and older, and adolescents is expected in Q1 2018 [19] Updated 27 Feb 2018
15 Dec 2017 Regulatory Status The Committee for Medicinal Products for Human Use (CHMP) recommends approval of burosumab for X-linked dominant hypophosphataemic rickets (In children, In infants, In adolescents) in European Union [19] Updated 18 Dec 2017
04 Dec 2017 Scientific Update Updated efficacy and adverse events data from a phase III trial in X-linked dominant hypophosphataemic rickets released by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin [47] Updated 06 Dec 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in X-linked dominant hypophosphataemic rickets in USA (IV, Injection) Updated 04 Nov 2017
02 Nov 2017 Scientific Update Updated efficacy data from a phase II trial in Osteomalacia released by Ultragenyx Pharmaceutical [9] Updated 08 Nov 2017
02 Nov 2017 Scientific Update Updated efficacy data from a phase III trial in X-linked dominant hypophosphataemic rickets released by Ultragenyx Pharmaceutical [9] Updated 08 Nov 2017
10 Oct 2017 Regulatory Status FDA assigns PDUFA action date of 17/04/2018 for burosumab for X-linked dominant hypophosphataemic rickets (In children, In infants, In adults) [7] Updated 23 May 2018
10 Oct 2017 Regulatory Status US FDA accepts BLA for burosumab for X-linked dominant hypophosphataemic rickets (In children, In adults, In infants) for priority review [7] Updated 12 Oct 2017
12 Sep 2017 Scientific Update Safety and efficacy data from a phase II trial in Osteomalacia presented at the Annual Meeting of the American Society for Bone and Mineral Research (ASBMR-2017) [107] Updated 14 Sep 2017
12 Sep 2017 Scientific Update Safety and efficacy data from a phase II trial in X-linked dominant hypophosphataemic rickets presented at the Annual Meeting of the American Society for Bone and Mineral Research (ASBMR-2017) [107] Updated 13 Sep 2017
24 Aug 2017 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets (In children, In adults, In infants) in USA (SC) [8] Updated 29 Aug 2017
28 Jul 2017 Regulatory Status Kyowa Hakko Kirin intends to file burosumab for approval with the EMA for adult X-linked hypophosphatemia [21] Updated 27 Feb 2018
28 Jul 2017 Regulatory Status Kyowa Hakko Kirin modifies conditional marketing authorisation application to X-linked hypophosphataemia (In children, In infants) in European Union [21] Updated 03 Aug 2017
27 Jul 2017 Regulatory Status Burosumab receives rare paediatric disease designation for X-linked hypophosphataemia in USA [3] Updated 31 Jul 2017
06 Jul 2017 Phase Change - III Phase-III clinical trials in Osteomalacia in Japan (SC) (NCT03233126) Updated 18 Dec 2017
06 Jul 2017 Trial Update Kyowa Hakko Kirin Pharma initiate a phase III trial for X-linked dominant hypophosphataemic rickets and Osteomalacia (In infants, In children) in Japan (JapicCTI-173614) (NCT03233126) Updated 17 Aug 2017
23 Jun 2017 Regulatory Status The US FDA agrees to accept available clinical data for BLA submission for paediatric and adult X-linked hypophosphataemia [10] Updated 30 Jun 2017
22 Jun 2017 Trial Update Kyowa Hakko Kirin Pharma plans a phase III trial for X-linked dominant hypophosphataemic rickets and Osteomalacia (In infants, In children) in Japan (JapicCTI-173614) (NCT03233126) Updated 17 Aug 2017
15 Jun 2017 Regulatory Status Burosumab - Kyowa Hakko Kirin Pharma/Ultragenyx Pharmaceutical receives Orphan Drug status for Osteomalacia in USA [102] Updated 18 Dec 2017
04 May 2017 Scientific Update Efficacy data from a phase III trial in X-linked dominant hypophosphataemic rickets released by Ultragenyx Pharmaceutical [49] Updated 17 May 2017
18 Apr 2017 Scientific Update Efficacy and adverse events data from a phase III trial in X-linked dominant hypophosphataemic rickets released by Ultragenyx Pharmaceutical [44] Updated 21 Apr 2017
06 Apr 2017 Scientific Update Efficacy and adverse events data from a phase II trial in X-linked dominant hypophosphataemic rickets released by Ultragenyx Pharmaceutical [59] Updated 24 Apr 2017
06 Apr 2017 Scientific Update Interim efficacy and adverse events data from phase II trial in X-linked dominant hypophosphataemic rickets released by Ultragenyx Pharmaceutical [59] Updated 24 Apr 2017
16 Feb 2017 Regulatory Status Ultragenyx announces intention to submit BLA for paediatric and adult X-linked hypophosphataemia to the USFDA in the second half of 2017 [22] Updated 29 Aug 2017
05 Jan 2017 Regulatory Status European Medicines Agency accepts MAA for X-linked dominant hypophosphataemic rickets (In adults, In children, In infants) for review [23] Updated 06 Jan 2017
31 Dec 2016 Phase Change - Preregistration Preregistration for X-linked dominant hypophosphataemic rickets (In children, In adults, In infants) in European Union prior to December 2016 (SC) [23] Updated 06 Jan 2017
22 Dec 2016 Trial Update Ultragenyx Pharmaceutical completes a phase III trial in X-linked Hypophosphatemia (In adults) in USA, France, Ireland, Italy, Japan, South Korea and United Kingdom (NCT02526160) Updated 28 Dec 2018
07 Nov 2016 Regulatory Status Ultragenyx announces intention to submit BLA for X-linked hypophosphataemia to US FDA in H2 2017 [11] Updated 19 Nov 2016
19 Sep 2016 Scientific Update Interim safety and efficacy data from phase II adult extention study in X-linked dominant hypophosphataemic rickets released by Ultragenyx [68] Updated 14 Oct 2016
19 Sep 2016 Scientific Update Updated safety and efficacy data from phase II tral in X-linked dominant hypophosphataemic rickets (In children) released by Ultragenyx [68] Updated 14 Oct 2016
18 Sep 2016 Scientific Update Updated positive interim efficacy and adverse events data from a phase II trial in Osteomalacia released by Ultragenyx [95] Updated 24 Jan 2017
16 Sep 2016 Scientific Update Interim efficacy data from a phase II trial in Osteomalacia presented at the 38th Annual Meeting of the American Society for Bone and Mineral Research-2016 (ASBMR-2016) [97] Updated 02 Jan 2017
15 Sep 2016 Phase Change - III Phase-III clinical trials in X-linked dominant hypophosphataemic rickets (In children, In infants) in Germany (SC) after September 2016 Updated 17 Nov 2016
15 Sep 2016 Phase Change - III Phase-III clinical trials in X-linked dominant hypophosphataemic rickets (In infants, In children) in Denmark, Ireland, Spain, Sweden (SC) (EudraCT2016-000600-29) Updated 06 Oct 2016
01 Sep 2016 Phase Change - III Phase-III clinical trials in X-linked dominant hypophosphataemic rickets (In children, In infants) in United Kingdom (SC) after September 2016 (NCT02915705) Updated 29 Aug 2017
01 Sep 2016 Trial Update Ultragenyx Pharmaceutical and Kyowa Hakko Kirin Pharma initiate a phase III trial in X-linked dominant hypophosphataemic rickets (In children, In infants) in South Korea, Italy (SC) after September 2016 (NCT02915705) Updated 29 Aug 2017
01 Sep 2016 Phase Change - III Phase-III clinical trials in X-linked dominant hypophosphataemic rickets (In children, In infants) in Canada, Australia, Japan (SC) (NCT02915705) (Kyowa Hakko Kirin pipeline, February 2017) Updated 13 Feb 2017
01 Sep 2016 Phase Change - III Phase-III clinical trials in X-linked dominant hypophosphataemic rickets (In children, In infants) in USA (SC) (NCT02915705) Updated 06 Oct 2016
28 Jul 2016 Trial Update Ultragenyx Pharmaceutical completes enrolment in a phase-III trial in X-linked dominant hypophosphataemic rickets in USA, Ireland, Japan, South Korea, Denmark, France, Italy, United Kingdom, Canada [45] Updated 01 Aug 2016
28 Jun 2016 Regulatory Status Burosumab receives Breakthrough Therapy status for X-linked dominant hypophosphataemic rickets (In children, In infants) in USA [37] Updated 30 Jun 2016
01 May 2016 Phase Change - II Phase-II clinical trials in X-linked dominant hypophosphataemic rickets (In children, In infants) in USA (SC) (NCT02750618) Updated 25 May 2016
21 Apr 2016 Scientific Update Interim safety, efficacy and pharmacodynamics data from a phase II trial in tumour-induced osteomalacia and epidermal nevus syndrome released by Ultragenyx Pharmaceutical [96] Updated 27 Apr 2016
20 Apr 2016 Trial Update Ultragenyx Pharmaceutical plans a phase II trial for X-linked dominant hypophosphataemic rickets (In infants, In children) in USA (SC) (NCT02750618) Updated 29 Apr 2016
01 Apr 2016 Phase Change - II Phase-II clinical trials in Nevus in Japan (SC) Updated 17 Nov 2016
01 Apr 2016 Phase Change - II Phase-II clinical trials in Nevus in South Korea (SC) Updated 17 Nov 2016
01 Apr 2016 Phase Change - II Phase-II clinical trials in Osteomalacia in Japan (SC) Updated 17 Nov 2016
01 Apr 2016 Phase Change - II Phase-II clinical trials in Osteomalacia in South Korea (SC) Updated 17 Nov 2016
01 Apr 2016 Scientific Update Interim adverse events and efficacy data from a phase II trial in X-Linked hypophosphataemia presented at The 98th Annual Meeting of the Endocrine Society (ENDO-2016) [67] Updated 29 Jul 2016
23 Mar 2016 Trial Update Kyowa Hakko Kirin Company plans a phase II trial for Nevus and Osteomalacia in Japan and South Korea (SC) (NCT02722798) Updated 04 Apr 2016
02 Dec 2015 Scientific Update Interim efficacy and adverse events data from a phase II trial in X-linked dominant hypophosphataemic rickets released by Kyowa Hakko Kirin [24] Updated 08 Dec 2015
02 Dec 2015 Regulatory Status Kyowa Hakko Kirin and Ultragenyx announces intention to submit MAA to EMA [24] Updated 07 Dec 2015
02 Dec 2015 Trial Update Ultragenyx Pharmaceutical and Kyowa Hakko Kirin Company plan the phase III PIXLES trial for X-linked dominant hypophosphataemic rickets (In infants, In children) in USA, Australia, European Union, South Korea, Canada and Japan (SC) [24] , NCT02915705) Updated 07 Dec 2015
01 Dec 2015 Trial Update Ultragenyx Pharmaceutical initiates enrolment a phase III trial in X-linked dominant hypophosphataemic rickets (In adults) in Canada, Denmark, France, Japan, and South Korea after December 2015 (NCT02537431) Updated 17 May 2017
01 Dec 2015 Trial Update Kyowa Hakko Kirin completes a phase I trial in X-linked dominant hypophosphataemic rickets in Japan and South Korea (SC) (NCT02181764) Updated 31 Mar 2016
01 Dec 2015 Trial Update Ultragenyx Pharmaceutical initiates a phase III trial in X-linked dominant hypophosphataemic rickets in USA (NCT02537431) Updated 16 Dec 2015
01 Dec 2015 Phase Change - III Phase-III clinical trials in X-linked dominant hypophosphataemic rickets in USA (SC) Updated 05 Dec 2015
02 Oct 2015 Active Status Review Burosumab is still in phase I/II trials for X-linked dominant hypophosphataemic rickets in Canada Updated 02 Oct 2015
01 Oct 2015 Phase Change - III Phase-III clinical trials in X-linked dominant hypophosphataemic rickets (In adults) in Denmark, France, Italy, United Kingdom, Canada (SC) after October 2015 Updated 01 Aug 2016
01 Oct 2015 Phase Change - III Phase-III clinical trials in X-linked dominant hypophosphataemic rickets (In adults) in Ireland, Japan, South Korea (SC) after October 2015 Updated 15 Feb 2016
24 Sep 2015 Trial Update Ultragenyx in collaboration with Kyowa Hakko Kirin plans a phase III trial for X-linked Hypophosphataemia (In adults) in Canada, European Union, Japan, South Korea and USA (NCT02526160) Updated 24 Sep 2015
09 Jul 2015 Scientific Update Updated efficacy and safety data from a phase II trial in X-linked dominant hypophosphataemic rickets (In children) released by Ultragenyx Pharmaceutical [61] Updated 15 Jul 2015
02 Jun 2015 Scientific Update Interim 16-week data from a phase II trial (paediatric patients) in X-linked dominant hypophosphataemic rickets released by Ultragenyx [25] Updated 07 Jul 2015
25 Mar 2015 Phase Change - II Phase-II clinical trials in Nevus in USA (SC) Updated 15 Apr 2015
25 Mar 2015 Phase Change - II Phase-II clinical trials in Osteomalacia in USA (SC) Updated 15 Apr 2015
12 Mar 2015 Phase Change - II Phase-II clinical trials in X-linked dominant hypophosphataemic rickets in USA (SC) (NCT02312687) Updated 14 May 2015
12 Dec 2014 Trial Update Ultragenyx and Kyowa Hakko Kirin plan a phase IIb extension trial for X-linked dominant hypophosphataemic rickets in USA (NCT02312687) Updated 12 Dec 2014
24 Nov 2014 Trial Update Ultragenyx and Kyowa Hakko Kirin plan a phase II trial for Nevus and Osteomalacia in USA (NCT02304367) Updated 05 Dec 2014
10 Nov 2014 Trial Update Ultragenix completes enrolment in a phase II trial in X-linked dominant hypophosphataemic rickets (paediatric patients) in the US and Europe (NCT02163577) [63] Updated 10 Dec 2014
30 Oct 2014 Regulatory Status Burosumab receives Orphan Drug status for X-linked dominant hypophosphataemic rickets in European Union [85] Updated 01 Nov 2014
15 Sep 2014 Scientific Update Cumulative efficacy and adverse events data from two phase I/II trials in X-linked dominant hypophosphataemic rickets presented at the Annual Meeting of the American Society of Bone and Mineral Research (ASBMR-2014) [77] , [76] Updated 17 Sep 2014
29 Jul 2014 Phase Change - I Phase-I clinical trials in X-linked dominant hypophosphataemic rickets in Japan and South Korea (SC) (NCT02181764) Updated 30 Jul 2014
25 Jul 2014 Phase Change - II Phase-II clinical trials in X-linked dominant hypophosphataemic rickets (in children aged 5 to 12 years) in France (SC) [65] Updated 28 Jul 2014
25 Jul 2014 Phase Change - II Phase-II clinical trials in X-linked dominant hypophosphataemic rickets (in children aged 5 to 12 years) in Netherlands (SC) [65] Updated 28 Jul 2014
25 Jul 2014 Phase Change - II Phase-II clinical trials in X-linked dominant hypophosphataemic rickets (in children aged 5 to 12 years) in United Kingdom (SC) [65] Updated 28 Jul 2014
25 Jun 2014 Trial Update Kyowa Hakko Kirin completes a phase I/II trial in X-linked dominant hypophosphataemic rickets in USA and Canada (NCT01571596) Updated 18 Jul 2014
24 Jun 2014 Scientific Update Safety and efficacy data from a phase I/II trial in X-linked Hypophosphatemia presented at the Joint meeting of the 16th International Society of Endocrinology and the 96th Annual Meeting of the Endocrine Society (ICE/ENDO-2014) [73] Updated 15 Jul 2014
01 Jun 2014 Phase Change - II Phase-II clinical trials in X-linked dominant hypophosphataemic rickets (in children aged 5 to 12 years) in USA (SC) Updated 04 Jul 2014
31 Oct 2013 Trial Update Kyowa Hakko Kirin completes enrolment in its phase I/II extension trial for X-linked dominant hypophosphataemic rickets in USA and Canada (NCT01571596) Updated 02 Apr 2014
31 Oct 2013 Trial Update Kyowa Hakko Kirin completes a phase I/II trial in X-linked dominant hypophosphataemic rickets in USA and Canada (NCT01340482) Updated 02 Apr 2014
06 Oct 2013 Scientific Update Pharmacodynamics & adverse events data from a phase I trial in X-linked dominant hypophosphataemic rickets presented at the American Society of Bone Mineralization Research Annual Meeting (ASBMR-2013) [83] , [82] Updated 10 Oct 2013
05 Sep 2013 Active Status Review Phase-I/II development is ongoing in USA & Canada Updated 05 Sep 2013
03 Sep 2013 Licensing Status Ultragenyx Pharmaceutical & Kyowa Hakko Kirin agree to co-promote & co-develop burosumab for X-linked dominant hypophosphataemic rickets [4] Updated 05 Sep 2013
29 Feb 2012 Trial Update Kyowa Hakko Kirin initiates enrolment in a phase I/II extension trial for X-linked dominant hypophosphataemic rickets in USA (NCT01571596) Updated 20 Apr 2012
06 Dec 2011 Phase Change - I/II Phase-I/II clinical trials in X-linked dominant hypophosphataemic rickets in Canada (SC) Updated 24 Feb 2012
06 Dec 2011 Trial Update Kyowa Hakko Kirin completes a phase I trial in X-linked dominant hypophosphataemic rickets in USA (NCT00830674) Updated 24 Feb 2012
15 Apr 2011 Phase Change - I/II Phase-I/II clinical trials in X-linked dominant hypophosphataemic rickets in USA (SC) Updated 27 Apr 2011
15 Dec 2010 Phase Change - I Phase-I clinical trials in X-linked dominant hypophosphataemic rickets in USA (SC) Updated 27 Apr 2011
14 Dec 2009 Regulatory Status Burosumab receives Orphan Drug status for X-linked dominant hypophosphataemic rickets in USA Updated 15 Jul 2014
31 Dec 2008 Phase Change - I Phase-I clinical trials in X-linked dominant hypophosphataemic rickets in USA (IV) Updated 28 Jul 2009

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  78. Announcement of Start of Phase 1 Joint Japanese-Korean Study of a Human Monoclonal Anti-FGF23 Antibody (KRN23) in X-linked Hypophosphatemic Rickets/Osteomalacia in Adults.

    Media Release
  79. A Phase 1, Multicenter, Open-label, Sequential Dose-escalation, Single-dose Study to Assess the Safety and Tolerability of KRN23 in Subjects With X-linked Hypophosphatemic Rickets/Osteomalacia.

    ctiprofile
  80. Ultragenyx Announces the Presentation of Data From a Single Dose Phase 1 Study, Conducted by Kyowa Hakko Kirin Co. Ltd. (KHK), of KRN23 in X-linked Hypophosphatemia (XLH) in Adults.

    Media Release
  81. Announcement of Results from a Single Dose Phase 1 Study of a Human Monoclonal Anti-FGF23 Antibody (KRN23) in X-linked Hypophosphatemia in Adults.

    Media Release
  82. A Phase I, Double-blind, Randomized, Placebo-controlled, Single-dose, Dose-escalation Study of KRN23 in X-linked Hypophosphatemia

    ctiprofile
  83. Ultragenyx Granted EU Orphan Drug Designation for KRN23 for the Treatment of X-Linked Hypophosphatemia.

    Media Release
  84. Ultragenyx Reports Third Quarter 2020 Financial Results and Corporate Update.

    Media Release
  85. Ultragenyx and Kyowa Kirin Announce U.S. FDA Approval of Crysvita(Rm) (burosumab) for the Treatment of Tumor-Induced Osteomalacia (TIO).

    Media Release
  86. Ultragenyx Reports First Quarter 2020 Financial Results and Corporate Update.

    Media Release
  87. Ultragenyx Reports Fourth Quarter and Full Year 2019 Financial Results and Corporate Update.

    Media Release
  88. Ultragenyx and Kyowa Kirin Announce Intent to Submit Supplemental Biologics License Application to U.S. FDA for Crysvita(Rm) (burosumab) in Tumor-Induced Osteomalacia (TIO).

    Media Release
  89. MEDIA ADVISORY: Ultragenyx Canada Announces Health Canada Approval of a Second Indication for Crysvita(Tm) (Burosumab Injection) for the Treatment of Tumour Induced Osteomalacia in Adults.

    Media Release
  90. Ultragenyx Reports Second Quarter 2015 Financial Results and Corporate Update.

    Media Release
  91. Ultragenyx Initiates New Development Program Studying KRN23 for the Treatment of Tumor-Induced Osteomalacia.

    Media Release
  92. A Phase 2 Open-Label Trial to Assess the Efficacy and Safety of KRN23, an Antibody to FGF23, in Subjects With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)-Associated Osteomalacia

    ctiprofile
  93. Ultragenyx Reports Positive Interim Data from Phase 2 Study of KRN23 for the Treatment of Tumor-Induced Osteomalacia 18/09/16.

    Media Release
  94. Ultragenyx Reports Positive Interim Data from Phase 2 Study of KRN23 for the Treatment of Tumor-Induced Osteomalacia.

    Media Release
  95. Carpenter T, Miller P, Weber T, Peacock M, Ruppe M, Insogna K, et al. Effects of KRN23, an Anti-FGF23 Antibody, in Patients With Tumor Induced Osteomalacia and Epidermal Nevus Syndrome: Results from an Ongoing Phase 2 Study. ASBMR-2016 2016; abstr. 1098.

    Available from: URL: http://www.asbmr.org/education/AbstractDetail?aid=bda2a3aa-4d02-444b-84b6-6f8b3d854519
  96. De Beur SMJ, Miller PD, Weber TJ, Peacock M, Insogna KL, Kumar R, et al. Burosumab Improves the Biochemical, Skeletal, and Clinical Symptoms of Tumor-Induced Osteomalacia Syndrome. ENDO-2019 2019; abstr. OR13-1.

  97. FDA Approves First Therapy for Rare Disease that Causes Low Phosphate Blood Levels, Bone Softening.

    Media Release
  98. Carpenter TO, Miller PD, Weber TJ, Peacock M, Insogna KL, Kumar R, et al. Burosumab Improves Biochemical, Skeletal, and Clinical Features of Tumor-Induced Osteomalacia Syndrome. ENDO-2020 2020; abstr. OR29-06.

    Available from: URL: https://academic.oup.com/jes/article/4/Supplement_1/OR29-06/5832346
  99. A Phase 2 Open-Label Trial to Assess the Efficacy and Safety of KRN23 in Patients With Tumor-Induced Osteomalacia or Epidermal Nevus Syndrome

    ctiprofile
  100. Burosumab: Orphan Drug Designation for Osteomalacia. Internet-Doc 2017;.

    Available from: URL: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/listResult.cfm
  101. Ultragenyx Announces Pricing of Public Offering of Common Stock.

    Media Release
  102. Ultragenyx Pharmaceutical 10-K March 2021. Internet-Doc 2021;.

    Available from: URL: https://www.sec.gov/ix?doc=/Archives/edgar/data/1515673/000156459021005610/rare-10k_20201231.htm
  103. Whyte M, Imel EA, Portale AA, Boot A, Hogler W, Linglart A, et al. Burosumab, A Fully Human Anti-FGF23 Monoclonal Antibody, For X-linked Hypophosphatemia (xlh): Results From Two Phase 2 Trials In Affected Children 1-12 Years Old. ENDO-2018 2018; abstr. MON-473.

    Available from: URL: http://link.adisinsight.com/y8Y7J
  104. Ultragenyx Reports Fourth Quarter and Full Year 2017 Financial Results and Corporate Update.

    Media Release
  105. Ultragenyx and Kyowa Hakko Kirin Announce Additional Burosumab Data in X-Linked Hypophosphatemia (XLH) and Tumor-Induced Osteomalacia (TIO) at ASBMR.

    Media Release
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