6/22/2018 Burosumab - DrugBank

Burosumab

Targets (1) Biointeractions (1)

IDENTIFICATION

Name Burosumab

Accession Number DB14012

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies Monoclonal antibody (mAb)

Description

Burosumab (KRN23) is an entirely human monoclonal IgG1 antibody that binds excess fibroblast growth factor 23 (FGF23) and has been successfully tested in clinical trials in children with X- linked hypophosphatemic rickets [1].

The U.S. Food and Drug Administration approved Crysvita (burosumab) in April 2018. This is the first drug approved to treat adults and children ages 1 year and older with X-linked hypophosphatemia (XLH), which is a rare, inherited form of rickets. X-linked hypophosphatemia causes low circulating levels of phosphorus in the blood. It causes impaired bone growth and development in children and adolescents and issues with bone mineralization throughout a patient’s life [3].

XLH is a serious disease which affects about 3,000 children and 12,000 adults in the United States. Most children with XLH suffer from bowed or bent legs, short stature, bone pain and severe dental pain. Some adults with this condition suffer from persistent, unrelenting discomfort and complications, such as joint pain, impaired mobility, tooth abscesses and hearing loss [3].

Protein chemical formula

C6388H9904N1700O2006S46 https://www.drugbank.ca/drugs/DB14012 1/10 6/22/2018 Burosumab - DrugBank C6388H9904N1700O2006S46

Protein average weight 144100.0 Da

Sequences

> Burosumab Heavy Chain Sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTNHYMHWVRQAPGQGLEWMGIINPISGSTSN AQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDIVDAFDFWGQGTMVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK

> Burosumab Light Chain Sequence AIQLTQSPSSLSASVGDRVTITCRASQGISSALVWYQQKPGKAPKLLIYDASSLESGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQFNDYFTFGPGTKVDIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Download FASTA Format

Synonyms

Burosumab (genetical recombination)

burosumab-twza

External IDs

KRN-23 / KRN23

Prescription Products

Search

MARKETING MARKETING NAME ↑↓ DOSAGE ↑↓ STRENGTH ↑↓ ROUTE ↑↓ LABELLER ↑↓ START ↑↓ END ↑↓ ↑↓ ↑↓

Crysvita Injection 10 mg/mL Subcutaneous Ultragenyx 2018-04-18 Not applicable Pharmaceutical Inc.

Crysvita Injection 30 mg/mL Subcutaneous Ultragenyx 2018-04-18 Not applicable Pharmaceutical Inc.

Crysvita Injection 20 mg/mL Subcutaneous Ultragenyx 2018-04-18 Not applicable Pharmaceutical Inc.

Showing 1 to 3 of 3 entries ‹ › https://www.drugbank.ca/drugs/DB14012 2/10 6/22/2018 Burosumab - DrugBank

Categories Not Available

UNII G9WJT6RD29

CAS number 1610833-03-8

PHARMACOLOGY

Indication This drug is indicated for the treatment of X-linked hypophosphatemia with radiological evidence of bone disease in children of 1 year of age and older and adolescents with growing skeletons [4].

Pharmacodynamics

This drug has the ability to reduce the loss of phosphate, to improve pathologically low serum phosphate concentrations and other metabolic changes, as well as to reduce the severity of rickets as seen radiographically [5]. In summary, this drug works to support of bone mineralization [4].

Mechanism of action

Burosumab is a recombinant human monoclonal antibody (IgG1) that both binds to and inhibits the actions of fibroblast growth factor 23 (FGF23). By inhibiting this growth factor, burosumab increases the tubular reabsorption of phosphate from the kidney and thus increases serum concentration of 1, 25 dihydroxy-Vitamin D [4]. This form of vitamin D enhances intestinal absorption of phosphate and calcium, supporting bone mineralization [8].

A Fibroblast growth factor 23

antagonist

Human

Absorption

Burosumab absorption aer subcutaneous injection sites into to the blood circulation is nearly complete. Following the subcutaneous route of administration, the time to reach maximum serum concentrations (Tmax) of burosumab is estimated at 5-10 days. The peak serum concentration (Cmax) and area under the concentration-time curve (AUC) of serum burosumab is proportional to the dose, over the dose range of 0.1-2.0 mg/kg [4].

Volume of distribution

Burosumab is comprised solely of amino acids and carbohydrates as a native immunoglobulin and

is not likeluy to be eliminated by hepatic metabolic mechanisms. The metabolism of burosumab and elimination are expected to follow the immunoglobulin clearance pathways, which results in its degradation to smaller peptides and amino acids [4] https://www.drugbank.ca/drugs/DB14012 3/10 6/22/2018 Burosumab - DrugBank its degradation to smaller peptides and amino acids [ ].

Protein binding Not Available

Metabolism

Burosumab is composed solely of amino acids and carbohydrates as a native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids [4].

Route of elimination Because of its molecular size, burosumab is not likely to be directly excreted [4].

Half life About 19 days [4].

Clearance

The clearance of burosumab depends on weight and is estimated to be 0.290 L/day and 0.136 L/day in a typical adult (70 kg) and pediatric (30 kg) XLH patient, respectively [4].

Toxicity

The toxicity of Crysvita can be classified into several categories [4]:

Ectopic mineralisation: Clinically manifested by nephrocalcinosis, has been seen in patients with XLH treated with oral phosphorous and vitamin D analogues. These drugs should be stopped at least 1 week before starting burosumab treatment [4].

Monitoring for signs and symptoms of nephrocalcinosis, e.g. by renal ultrasonography, is recommended at the beginning of treatment and at intervals of every 6 months for the first 12 months of treatment, and yearly thereaer. Regular monitoring of plasma alkaline phosphatases, Calcium, PTH, and creatinine is advised at 6 months intervals(every 3 months for children 1- 2 years) or as indicated [4].

Monitoring of urine calcium and phosphate is suggested every 3 months.

Hyperphosphatemia

Fasting serum phosphate level must be followed due to the risk of hyperphosphatemia while taking this drug. To decrease the risk for ectopic mineralization, it is advised that fasting serum phosphate is aimed to be in the lower end of the normal reference range for any given age. Dose interruption and/or dose reduction may be required. Regular measurement of postprandial serum phosphate is advised [4].

Serum parathyroid hormone increases

Increases in serum parathyroid hormone have been measured in some XLH patients while undergoing treatment with burosumab Regular measurement of serum parathyroid hormone is https://www.drugbank.ca/drugs/DB14012 4/10 6/22/2018 Burosumab - DrugBank undergoing treatment with burosumab. Regular measurement of serum parathyroid hormone is recommended [4].

Injection site reactions

Administration of burosumab, like other injections, can lead to local injection site reactions. Administration of this drug should cease in any patient experiencing severe injection site reactions and appropriate medical therapy administered [4].

Hypersensitivity

Burosumab should be discontinued if serious hypersensitivity reactions occur and appropriate medical treatment should be provided [4].

Reproductive toxicity/pregnancy

There are no or limited amount of data available from the use of burosumab in pregnant women. Studies in animals have demonstrated reproductive toxicity. Burosumab use is not advised during pregnancy and in women of childbearing potential/age currently not using contraception [4].

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

INTERACTIONS

Drug Interactions

Not Available

Food Interactions

Not Available

REFERENCES

General References

1. Kutilek S: Burosumab: A new drug to treat hypophosphatemic rickets. Sudan J Paediatr. 2017;17(2):71-73. doi: 10.24911/SJP.2017.2.11. [PubMed:29545670] 2. Kinoshita Y, Fukumoto S: X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases -Prospect for new treatment. Endocr Rev. 2018 Jan 26. pii: 4825438. doi: 10.1210/er.2017-00220. [PubMed:29381780] 3. FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia [Link] 4. Crysvita Drug Label [Link] 5. Burosumab for a rare bone disease [Link] 6. DRUG: Burosumab [Link] https://www.drugbank.ca/drugs/DB14012 5/10 6/22/2018 Burosumab - DrugBank 7. NHS document [Link] 8. Burosumab for XLH [Link]

External Links KEGG Drug D10913

Wikipedia Burosumab

CLINICAL TRIALS

Clinical Trials

Search

PHASE ↑↓ STATUS ↑↓ PURPOSE ↑↓ CONDITIONS ↑↓ COUNT ↑↓ 1 Completed Treatment X-Linked Hypophosphatemia 1

1 Completed Treatment X-linked Hypophosphatemic Rickets/Osteomalacia 1

1, 2 Completed Treatment X-Linked Hypophosphatemia 2

2 Active Not Treatment Epidermal Nevus Syndrome (ENS) / Tumor Induced 1 Recruiting Osteomalacia (TIO)

2 Active Not Treatment Tumor-Induced Osteomalacia or Epidermal Nevus 1 Recruiting Syndrome

2 Active Not Treatment X-Linked Hypophosphatemia 3 Recruiting

3 Active Not Treatment X-Linked Hypophosphatemia 3 Recruiting

3 Active Not Treatment X-linked Hypophosphatemic Rickets/Osteomalacia 1 Recruiting

Showing 1 to 8 of 8 entries ‹ ›

PHARMACOECONOMICS

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

https://www.drugbank.ca/drugs/DB14012 6/10 6/22/2018 Burosumab - DrugBank

Search

FORM ↑↓ ROUTE ↑↓ STRENGTH ↑↓ Injection Subcutaneous 10 mg/mL

Injection Subcutaneous 20 mg/mL

Injection Subcutaneous 30 mg/mL

Showing 1 to 3 of 3 entries ‹ ›

Prices Not Available

Patents Not Available

PROPERTIES

State

Solid

Experimental Properties

Not Available

TAXONOMY

Description

Not Available

Kingdom

Organic Compounds

Super Class

Organic Acids

Class

Carboxylic Acids and Derivatives

Sub Class

Amino Acids, Peptides, and Analogues

Direct Parent https://www.drugbank.ca/drugs/DB14012 7/10 6/22/2018 Burosumab - DrugBank Peptides

Alternative Parents Not Available

Substituents Not Available

Molecular Framework Not Available

External Descriptors Not Available

TARGETS

1. Fibroblast growth factor 23

Kind

Protein

Organism Human

Pharmacological action

Yes

Actions

Antagonist General Function

Not Available

Specific Function

Fibroblast growth factor receptor binding

Gene Name

FGF23

Uniprot ID

Q7Z4T2

Uniprot Name

Fibroblast growth factor 23

Molecular Weight

16440.335 Da https://www.drugbank.ca/drugs/DB14012 8/10 6/22/2018 Burosumab - DrugBank

References

1. Tardy B, Lecompte T, Boelhen F, Tardy-Poncet B, Elalamy I, Morange P, Gruel Y, Wolf M, Francois D, Racadot E, Camarasa P, Blouch MT, Nguyen F, Doubine S, Dutrillaux F, Alhenc-Gelas M, Martin-Toutain I, Bauters A, Ffrench P, de Maistre E, Grunebaum L, Mouton C, Huisse MG, Gouault-Heilmann M, Lucke V: Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood. 2006 Sep 1;108(5):1492-6. Epub 2006 May 11. [PubMed:16690967] 2. Kutilek S: Burosumab: A new drug to treat hypophosphatemic rickets. Sudan J Paediatr. 2017;17(2):71-73. doi: 10.24911/SJP.2017.2.11. [PubMed:29545670] 3. Crysvita Drug Label [Link] 4. Burosumab for XLH [Link] 5. Burosumab for a rare bone disease [Link] 6. DRUG: Burosumab [Link]

Drug created on April 18, 2018 09:27 / Updated on June 02, 2018 08:58

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This project is supported by the Canadian Institutes of Health Research (award #111062), Alberta Innovates - Health Solutions, and by The Metabolomics Innovation Centre (TMIC), a nationally-funded research and core facility that supports a wide range of cutting-edge metabolomic studies. TMIC is funded by Genome Alberta, Genome British

Columbia, and Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with https://www.drugbank.ca/drugs/DB14012 9/10 6/22/2018 Burosumab - DrugBank p g g g gy funding from the federal government. Maintenance, support, and commercial licensing is provided by OMx Personal Health Analytics, Inc. Designed by Educe Design & Innovation Inc.

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