Asfotase Alfa - Drugbank

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7/31/2018 Asfotase Alfa - DrugBank

Asfotase Alfa

Targets (2) Biointeractions (2)

IDENTIFICATION

Name Asfotase Alfa

Accession Number DB09105

Type

Biotech

Groups Approved, Investigational

Biologic Classiﬁcation Protein Based Therapies Fusion proteins

Description

Asfotase Alfa is a first-in-class bone-targeted enzyme replacement therapy designed to address the underlying cause of hypophosphatasia (HPP)—deficient alkaline phosphatase (ALP). Hypophosphatasia is almost always fatal when severe skeletal disease is obvious at birth. By replacing deficient ALP, treatment with Asfotase Alfa aims to improve the elevated enzyme substrate levels and improve the body's ability to mineralize bone, thereby preventing serious skeletal and systemic patient morbidity and premature death. Asfotase alfa was first approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on July 3, 2015, then approved by the European Medicine Agency (EMA) on August 28, 2015, and was approved by the U.S. Food and Drug Administration (FDA) on October 23, 2015. Asfotase Alfa is marketed under the brand name Strensiq® by Alexion Pharmaceuticals, Inc. The annual average price of Asfotase Alfa treatment is $285,000.

Protein structure https://www.drugbank.ca/drugs/DB09105 1/13 7/31/2018 Asfotase Alfa - DrugBank

Protein chemical formula

C7108H11008N1968O2206S56

Protein average weight 180000.0 Da (Approximate)

Sequences

> Asfotase Alfa Sequence LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQL HHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERS RCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEAL SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLDLVDTWK SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEMVVVAI QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTLTVVTA DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVSMVDYA HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACIGANLGHC APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKDIDDDD DDDDDD

Download FASTA Format

Synonyms

Asfotase alpha

External IDs

ALXN-1215 / ENB-0040 / sALP-FcD10 / UNII-Z633861EIM

Prescription Products

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

Strensiq Solution 18 mg/.45mL Subcutaneous Alexion 2015-10-23 Not applicable https://www.drugbank.ca/drugs/DB09105 2/13 7/31/2018 Asfotase Alfa - DrugBank Pharmaceuticals

Strensiq Solution 40 mg Subcutaneous Alexion Pharma Not applicable Not applicable Ghbh

Strensiq Injection, 40 mg/ml Subcutaneous Alexion Europe 2015-08-28 Not applicable solution Sas

Strensiq Injection, 100 mg/ml Subcutaneous Alexion Europe 2015-08-28 Not applicable solution Sas

Strensiq Solution 40 mg Subcutaneous Alexion Pharma 2016-06-01 Not applicable Gmbh

Strensiq Injection, 40 mg/ml Subcutaneous Alexion Europe 2015-08-28 Not applicable solution Sas

Strensiq Solution 40 mg/mL Subcutaneous Alexion 2015-10-23 Not applicable Pharmaceuticals

Strensiq Solution 40 mg Subcutaneous Alexion Pharma 2016-06-07 Not applicable Gmbh

Strensiq Injection, 40 mg/ml Subcutaneous Alexion Europe 2015-08-28 Not applicable solution Sas

Showing 1 to 10 of 19 entries ‹ ›

Categories

Alimentary Tract and Metabolism

Amino Acids, Peptides, and Proteins

Antibodies

Blood Proteins

Enzyme Replacement Therapy

Enzymes

Enzymes and Coenzymes

Esterases

Globulins

Hydrolases

Hypophosphatasia, drug therapy

Immunoglobulin Isotypes

Immunoglobulins https://www.drugbank.ca/drugs/DB09105 3/13 7/31/2018 Asfotase Alfa - DrugBank

Immunoproteins

Phosphoric Monoester Hydrolases

Proteins

Recombinant Proteins

Serum Globulins

Tissue-nonspeciﬁc Alkaline Phosphatase

UNII

Z633861EIM

CAS number

1174277-80-5

PHARMACOLOGY

Indication Indicated for the treatment of patients with perinatal/infantile and juvenile onset hypophosphatasia (HPP).

Associated Conditions

Infantile-onset Hypophosphatasia

Juvenile-onset Hypophosphatasia

Perinatal-onset Hypophosphatasia

Pharmacodynamics Perinatal/infantile- and juvenile-onset HPP patients treated with Asfotase alfa had reductions in plasma TNSALP (tissue non-speciﬁc alkaline phosphatase) substrates, PPi and pyridoxal 5'- phosphate (PLP) within 6 to 12 weeks of treatment. Reductions in plasma PPi and PLP levels did not correlate with clinical outcomes. Bone biopsy data from perinatal/infantile-onset and juvenile- onset HPP patients treated with Asfotase alfa demonstrated decreases in osteoid volume and thickness indicating improved bone mineralization.

Mechanism of action HPP is caused by a deﬁciency in TNSALP (tissue non-speciﬁc alkaline phosphatase) enzyme activity, which leads to elevations in several TNSALP substrates, including inorganic pyrophosphate (PPi). Elevated extracellular levels of PPi block hydroxyapatite crystal growth which inhibits bone mineralization and causes an accumulation of unmineralized bone matrix

hi h if t i k t d b d f ti i i f t d hild d t l i https://www.drugbank.ca/drugs/DB09105 4/13 7/31/2018 Asfotase Alfa - DrugBank which manifests as rickets and bone deformation in infants and children and as osteomalacia (soening of bones) once growth plates close, along with muscle weakness. Replacement of the TNSALP enzyme upon Asfotase alfa treatment reduces the enzyme substrate levels.

A Sphingosine 1-phosphate receptor 1

agonist

Homo sapiens

A Pyrophosphate

ligand

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism Not Available

Route of elimination

Not Available

Half life

Approximately 5 days.

Clearance Not Available

Toxicity

There are no available human data on Asfotase Alfa use in pregnant women to inform a drug associated risk. In animal reproduction studies, Asfotase Alfa administered intravenously to pregnant rats and rabbits during the period of organogenesis showed no evidence of fetotoxicity, embryolethality or teratogenicity at doses causing plasma exposures up to 21 and 24 times, respectively, the exposure at the recommended human dose.

Aﬀected organisms

Humans and other mammals https://www.drugbank.ca/drugs/DB09105 5/13 7/31/2018 Asfotase Alfa - DrugBank

Pathways

Not Available

Pharmacogenomic Eﬀects/ADRs

Not Available

INTERACTIONS

Drug Interactions

DRUG DRUG ↑↓ INTERACTION ↑↓ GROUP ↑↓

Anthrax immune globulin human The therapeutic eﬃcacy of Anthrax immune globulin human Approved can be decreased when used in combination with Asfotase Alfa.

Bacillus calmette-guerin substrain The therapeutic eﬃcacy of Bacillus calmette-guerin substrain Approved, connaught live antigen connaught live antigen can be decreased when used in Investigational combination with Asfotase Alfa.

Bacillus calmette-guerin substrain The therapeutic eﬃcacy of Bacillus calmette-guerin substrain Approved tice live antigen tice live antigen can be decreased when used in combination with Asfotase Alfa.

BCG vaccine The therapeutic eﬃcacy of BCG vaccine can be decreased Investigational when used in combination with Asfotase Alfa.

Clostridium tetani toxoid antigen The therapeutic eﬃcacy of Clostridium tetani toxoid antigen Approved (formaldehyde inactivated) (formaldehyde inactivated) can be decreased when used in combination with Asfotase Alfa.

Corynebacterium diphtheriae The therapeutic eﬃcacy of Corynebacterium diphtheriae Approved toxoid antigen (formaldehyde toxoid antigen (formaldehyde inactivated) can be decreased inactivated) when used in combination with Asfotase Alfa.

G17DT The therapeutic eﬃcacy of G17DT can be decreased when Investigational used in combination with Asfotase Alfa.

GI-5005 The therapeutic eﬃcacy of GI-5005 can be decreased when Investigational used in combination with Asfotase Alfa.

Hepatitis A Vaccine The therapeutic eﬃcacy of Hepatitis A Vaccine can be Approved decreased when used in combination with Asfotase Alfa.

Hepatitis B Vaccine The therapeutic eﬃcacy of Hepatitis B Vaccine Approved, (Recombinant) (Recombinant) can be decreased when used in combination Withdrawn with Asfotase Alfa.

https://www.drugbank.ca/drugs/DB09105 6/13 7/31/2018 Asfotase Alfa - DrugBank Showing 1 to 10 of 26 entries ‹ ›

Food Interactions

Not Available

REFERENCES

General References

1. Whyte MP: Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016 Apr;12(4):233-46. doi: 10.1038/nrendo.2016.14. Epub 2016 Feb 19. [PubMed:26893260] 2. Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C: Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2016 Jan;101(1):334-42. doi: 10.1210/jc.2015-3462. Epub 2015 Nov 3. [PubMed:26529632] 3. Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H: Enzyme-replacement therapy in life- threatening hypophosphatasia. N Engl J Med. 2012 Mar 8;366(10):904-13. doi: 10.1056/NEJMoa1106173. [PubMed:22397652]

External Links KEGG Drug D10595

PubChem Substance

347910406

ChEMBL

CHEMBL2108311

RxList RxList Drug Page

Drugs.com Drugs.com Drug Page

ATC Codes A16AB13 — Asfotase alfa A16AB — Enzymes A16A — OTHER ALIMENTARY TRACT AND METABOLISM PRODUCTS A16 — OTHER ALIMENTARY TRACT AND METABOLISM PRODUCTS A — ALIMENTARY TRACT AND METABOLISM

AHFS Codes https://www.drugbank.ca/drugs/DB09105 7/13 7/31/2018 Asfotase Alfa - DrugBank AHFS Codes

44:00.00 — Enzymes

FDA label Download (1.25 MB)

CLINICAL TRIALS

Clinical Trials

PHASE ↑↓ STATUS ↑↓ PURPOSE ↑↓ CONDITIONS ↑↓ COUNT ↑↓ 1 Completed Treatment Hypophosphatasia (HPP) 1

1, 2 Completed Treatment Hypophosphatasia (HPP) 1

2 Completed Treatment Hypophosphatasia 4

2 Completed Treatment Hypophosphatasia (HPP) 2

2 Withdrawn Treatment Hypophosphatasia 1

2, 3 Completed Treatment Hypophosphatasia 1

4 Completed Treatment Hypophosphatasia 1

Not Available Approved for Marketing Not Available Hypophosphatasia 1

Showing 1 to 8 of 8 entries ‹ ›

PHARMACOECONOMICS

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

FORM ↑↓ ROUTE ↑↓ STRENGTH ↑↓ Injection, solution Subcutaneous 100 mg/ml

https://www.drugbank.ca/drugs/DB09105 8/13 7/31/2018 Asfotase Alfa - DrugBank

Injection, solution Subcutaneous 40 mg/ml

Solution Subcutaneous 100 mg

Solution Subcutaneous 18 mg/.45mL

Solution Subcutaneous 28 mg/.7mL

Solution Subcutaneous 40 mg

Solution Subcutaneous 40 mg/mL

Solution Subcutaneous 80 mg/.8mL

Showing 1 to 8 of 8 entries ‹ ›

Prices Not Available

Patents

PATENT NUMBER ↑↓ PEDIATRIC EXTENSION ↑↓ APPROVED ↑↓ EXPIRES (ESTIMATED) ↑↓ ↑↓ US7763712 No 2004-04-21 2026-07-15

Showing 1 to 1 of 1 entries ‹ ›

PROPERTIES

State Liquid

Experimental Properties

Not Available

TAXONOMY

Description Not Available

Kingdom https://www.drugbank.ca/drugs/DB09105 9/13 7/31/2018 Asfotase Alfa - DrugBank Organic Compounds

Super Class Organic Acids

Class Carboxylic Acids and Derivatives

Sub Class

Amino Acids, Peptides, and Analogues

Direct Parent

Peptides

Alternative Parents Not Available

Substituents

Not Available

Molecular Framework

Not Available

External Descriptors Not Available

TARGETS

1. Sphingosine 1-phosphate receptor 1

Kind Protein

Organism

Homo sapiens

Pharmacological action

Yes

https://www.drugbank.ca/drugs/DB09105 10/13 7/31/2018 Asfotase Alfa - DrugBank Actions

Agonist General Function Sphingosine-1-phosphate receptor activity

Speciﬁc Function

G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activatio...

Gene Name S1PR1

Uniprot ID P21453

Uniprot Name Sphingosine 1-phosphate receptor 1

Molecular Weight

42810.195 Da

References

1. Bolli MH, Abele S, Binkert C, Bravo R, Buchmann S, Bur D, Gatﬁeld J, Hess P, Kohl C, Mangold C, Mathys B, Menyhart K, Muller C, Nayler O, Scherz M, Schmidt G, Sippel V, Steiner B, Strasser D, Treiber A, Weller T: 2- imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. J Med Chem. 2010 May 27;53(10):4198-211. doi: 10.1021/jm100181s. [PubMed:20446681] 2. Piali L, Froidevaux S, Hess P, Nayler O, Bolli MH, Schlosser E, Kohl C, Steiner B, Clozel M: The selective sphingosine 1-phosphate receptor 1 agonist ponesimod protects against lymphocyte-mediated tissue inﬂammation. J Pharmacol Exp Ther. 2011 May;337(2):547-56. doi: 10.1124/jpet.110.176487. Epub 2011 Feb 23. [PubMed:21345969]

2. Pyrophosphate

Kind Small molecule Organism Not Available Pharmacological action Yes

Actions Ligand https://www.drugbank.ca/drugs/DB09105 11/13 7/31/2018 Asfotase Alfa - DrugBank References

1. Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H: Enzyme- replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012 Mar 8;366(10):904-13. doi: 10.1056/NEJMoa1106173. [PubMed:22397652]

Drug created on September 16, 2015 16:39 / Updated on July 31, 2018 04:23

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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 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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