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
Db09105
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
NameDosageStrengthRouteLabellerMarketing StartMarketing End
StrensiqInjection, solution40 mg/mlSubcutaneousAlexion Europe Sas2015-08-28Not applicableEu
StrensiqSolution28 mg/0.7mLSubcutaneousAlexion Pharmaceuticals, Inc.2015-10-23Not applicableUs
StrensiqSolution40 mgSubcutaneousAlexion Pharma Gmbh2015-10-20Not applicableCanada
StrensiqSolution40 mgSubcutaneousAlexion Pharma GhbhNot applicableNot applicableCanada
StrensiqInjection, solution40 mg/mlSubcutaneousAlexion Europe Sas2015-08-28Not applicableEu
StrensiqInjection, solution40 mg/mlSubcutaneousAlexion Europe Sas2015-08-28Not applicableEu
StrensiqInjection, solution100 mg/mlSubcutaneousAlexion Europe Sas2015-08-28Not applicableEu
StrensiqSolution80 mg/0.8mLSubcutaneousAlexion Pharmaceuticals, Inc.2015-10-23Not applicableUs
StrensiqSolution40 mgSubcutaneousAlexion Pharma Gmbh2016-06-07Not applicableCanada
StrensiqSolution18 mg/0.45mLSubcutaneousAlexion Pharmaceuticals, Inc.2015-10-23Not applicableUs
Categories
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
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 which manifests as rickets and bone deformation in infants and children and as osteomalacia (softening of bones) once growth plates close, along with muscle weakness. Replacement of the TNSALP enzyme upon Asfotase alfa treatment reduces the enzyme substrate levels.

TargetActionsOrganism
ASphingosine 1-phosphate receptor 1
agonist
Homo sapiens
APyrophosphate
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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Asfotase Alfa.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Asfotase Alfa.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Asfotase Alfa.
Anthrax immune globulin humanThe therapeutic efficacy of Anthrax immune globulin human can be decreased when used in combination with Asfotase Alfa.
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Asfotase Alfa.
Bacillus calmette-guerin substrain connaught live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Asfotase Alfa.
Bacillus calmette-guerin substrain tice live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Asfotase Alfa.
BasiliximabThe risk or severity of adverse effects can be increased when Basiliximab is combined with Asfotase Alfa.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Asfotase Alfa.
BevacizumabThe risk or severity of adverse effects can be increased when Bevacizumab is combined with Asfotase Alfa.
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
AHFS Codes
  • 44:00.00 — Enzymes
FDA label
Download (1.25 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHypophosphatasia (HPP)1
1, 2CompletedTreatmentHypophosphatasia (HPP)1
2CompletedTreatmentHypophosphatasia4
2CompletedTreatmentHypophosphatasia (HPP)2
2WithdrawnTreatmentHypophosphatasia1
2, 3CompletedTreatmentHypophosphatasia1
4CompletedTreatmentHypophosphatasia1
Not AvailableApproved for MarketingNot AvailableHypophosphatasia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous100 mg/ml
Injection, solutionSubcutaneous40 mg/ml
SolutionSubcutaneous100 mg
SolutionSubcutaneous18 mg/0.45mL
SolutionSubcutaneous28 mg/0.7mL
SolutionSubcutaneous40 mg
SolutionSubcutaneous40 mg/1mL
SolutionSubcutaneous80 mg/0.8mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7763712No2004-04-212026-07-15Us

Properties

State
Liquid
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
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Homo sapiens
Pharmacological action
Yes
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]
Kind
Small molecule
Organism
Not Available
Pharmacological action
Yes
Actions
Ligand
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 October 16, 2018 08:41