Type of information: Granting of a Market Authorisation in the EU
Product name: Crysvita® - burosumab (KRN23)
Compound: burosumab -recombinant human monoclonal IgG1 antibody for fibroblast growth factor 23
Therapeutic area: Rare diseases
- monoclonal antibody. KRN23 is an investigational recombinant fully human monoclonal IgG1 antibody, discovered by Kyowa Hakko Kirin, against the phosphaturic hormone fibroblast growth factor 23 (FGF23). It is being developed to treat X- linked hypophosphataemia. This inherited disorder is characterized by low levels of phosphate in the blood. The phosphate is abnormally processed in the kidneys, which causes a loss of phosphate in the urine and leads to soft, weak bones. In most cases, the signs and symptoms of hereditary hypophosphataemic rickets begin in early childhood. Characteristic features include bowed or bent legs, short stature, bone pain, and severe dental pain. The disease is characterized by excess activity of FGF23. This
- hormone reduces serum levels of phosphorus and vitamin D by regulating phosphate excretion and vitamin D production by the kidney. Phosphate wasting in XLH is caused by excessive levels and activity of FGF23.
- KRN23 is designed to bind to and thereby inhibit the excessive biological activity of FGF23. By blocking excess FGF23 in patients with XLH, KRN23 is intended to restore normal phosphate reabsorption from the kidney and increase the production of vitamin D, which enhances intestinal absorption of phosphate and calcium.
- Ultragenyx and Kyowa Hakko Kirin entered into a collaboration and license agreement in August 2013 to develop and commercialize KRN23.
Company: Ultragenyx Pharmaceutical (USA - CA) Kyowa Hakko Kirin (Japan)
Disease: X- linked hypophosphataemia
- • On December 15, 2017, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended granting a conditional marketing authorisation in the European Union for Crysvita® (burosumab) for the treatment of X-linked hypophosphataemia (XLH) with radiographic evidence of bone disease in children 1 year of age and older and adolescents with growing skeletons.
- The CHMP recommended conditional approval for the medicine. This is one of EU’s regulatory mechanisms to facilitate early access to medicines that fulfil unmet medical need. Conditional approval allows the Agency to recommend a medicine for marketing authorisation in the interest of public health where the benefit of its immediate availability to patients outweighs the risk inherent in the fact that additional data are still required. There is currently no authorised medicine available to treat this rare, serious, chronic and debilitating disease. Most children with XLH receive conventional therapy consisting of multiple daily doses of oral phosphate and active vitamin D analogues. The benefits of Crysvita® are its ability to reduce the loss of phosphate, improve abnormally low serum phosphate concentrations and other metabolic changes, and to reduce the severity of rickets as shown in x-rays .
- The CHMP’s recommendation is based on two phase II studies. The main study was conducted on 53 children aged 5-12 years. Children treated with Crysvita® experienced an improvement in their phosphate level and in the reabsorption of phosphate in their kidneys as well as radiographic improvement of rickets. In the second study of 13 patients age 1 to 4 years old receiving Crysvita®, the response was similar than in children in the main study. On this basis, the CHMP considered that efficacy results from age group 5-12 years can be extrapolated to ages 1 to 4 years old. As part of the conditional marketing authorisation, the applicant is required to complete three ongoing studies to further investigate the safety and efficacy of the medicine. The data from all three studies are planned to be submitted in or before 2020.The most common adverse reactions observed with Crysvita® were injection site reactions, headache, and pain in extremities.
- • On November 1, 2017, Ultragenyx Pharmaceutical , Kyowa Hakko Kirin and Kyowa Kirin International announced that the FDA has indicated in the "Day 74" filing communication that it is not currently planning to hold an advisory committee meeting to discuss the Biologics License Application (BLA) for burosumab to treat pediatric and adult patients with X-Linked Hypophosphatemia (XLH). Additionally, the FDA indicated that the review is proceeding according to its internal review timelines described in their Guidance on Good Review Management Principles and Practices for PDUFA Products.
- • On October 10, 2017, Ultragenyx Pharmaceutical, Kyowa Hakko Kirin and Kyowa Kirin International announced that the FDA has accepted the Biologics License Application (BLA) for burosumab to treat pediatric and adult patients with X-Linked Hypophosphatemia (XLH) and has granted Priority Review status. The Prescription Drug User Fee Act (PDUFA) action date for the BLA is April 17, 2018. The Agency has not informed the companies whether an advisory committee meeting to discuss the application will be needed. The FDA previously designated burosumab as a drug for a "rare pediatric disease", enabling issuance of a priority review voucher if burosumab is approved.
- • On August 24, 2017, Ultragenyx Pharmaceutical and Kyowa Hakko Kirin announced that Ultragenyx has submitted a Biologics License Application (BLA) with the FDA for burosumab to treat X-Linked Hypophosphatemia (XLH) in the US. The FDA will evaluate the submission and will decide on whether to accept it within 60 days, at which time the Prescription Drug User Fee Act (PDUFA) action date will be set.
- • On June 23, 2017, Ultragenyx Pharmaceutical announced that it has reached agreement with the FDA at a Pre-Biologics License Application (pre-BLA) meeting on the clinical package to support the burosumab (KRN23) BLA filing for X-linked hypophosphatemia (XLH). At the meeting, the FDA agreed that the BLA can be submitted based on available clinical data and confirmed that both pediatric and adult indications would be included in the review. Based on the agreement, the submission of the burosumab BLA is planned for the second half of 2017.
- • On June 28, 2016, Ultragenyx Pharmaceutical, a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, announced that it has received Breakthrough Therapy Designation from the FDA for KRN23 for the treatment of X-linked hypophosphatemia (XLH) in pediatric patients one year of age and older. This Breakthrough Therapy Designation is based on interim 40-week data from the first 36 patients enrolled in the ongoing pediatric Phase 2 study of KRN23 for the treatment of XLH. In addition to the ongoing Phase 2 study, Ultragenyx plans to initiate a Phase 3 study of KRN23 in pediatric patients with XLH in mid-2016. A Phase 3 program of KRN23 in adult patients with XLH is ongoing.
- • On July 9, 2015, Ultragenyx Pharmaceutical, announced that the FDA has granted Fast Track Designation to the KRN23 program in XLH.
- • On October 30, 2014, Ultragenyx Pharmaceutical announced that the European Commission has granted orphan medicinal product designation for recombinant human monoclonal IgG1 antibody for fibroblast growth factor 23 (KRN23 or UX023) for the treatment of X-linked hypophosphatemia (XLH). KRN23 is being developed under a license and collaboration agreement between Ultragenyx and Kyowa Hakko Kirin Co., Ltd. Multiple clinical studies in adult patients with XLH have been completed and a Phase 2 study in pediatric patients with XLH is ongoing. The FDA granted orphan drug designation for KRN23 in XLH in 2009.
Submission of marketing authorization application USA : 2017-08-24
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
UE authorization: 2018-02-19
Favourable opinion UE: 2017-12-14
Favourable opinion USA:
Orphan status USA: 2009-12-14
Orphan status UE: 2014-10-15
Pediatric exclusivit _USA:
Pediatric exclusivity UE: