Asfotase alfa

Last updated
Asfotase alfa
Clinical data
Trade names Strensiq
Other namesALXN-1215
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Routes of
administration 		Subcutaneous injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 46–98%
Elimination half-life ~5 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • None
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C7108H11008N1968O2206S56
Molar mass 161125.18 g·mol−1

Asfotase alfa, sold under the brand name Strensiq, is a medication used in the treatment of people with perinatal/infantile- and juvenile-onset hypophosphatasia. [4] [5] [6] [7] [8] [9] [10]

Contents

The most common side effects include injection site reactions, hypersensitivity reactions (such as difficulty breathing, nausea, dizziness and fever), lipodystrophy (a loss of fat tissue resulting in an indentation in the skin or a thickening of fat tissue resulting in a lump under the skin) at the injection site, and ectopic calcifications of the eyes and kidney. [6] [5]

The enzyme tissue non-specific alkaline phosphatase (ALP) plays a key role in creating and maintaining healthy bones, and managing calcium and phosphate in the body. People with hypophosphatasia cannot make enough working ALP, which leads to weak bones. Asfotase alfa is a version of the human ALP enzyme and serves as a replacement, thereby increasing levels of working ALP. [5]

Medical uses

In the United States, asfotase alfa is indicated for the treatment of people with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP). [4]

In the European Union, asfotase alfa is indicated for long-term enzyme replacement therapy in people with paediatric-onset hypophosphatasia to treat the bone manifestations of the disease. [5]

Adverse effects

The most common adverse effects in studies included injection site reactions (pain, itching, erythema, etc.), headache, limb pain, and haematoma. [4] [5] Possible rare side effects could not be assessed because of the low number of patients. [11] [4]

Interactions

Asfotase alfa interferes with alkaline phosphatase measurements. As asfotase alfa is a glycoprotein (as opposed to a small molecule), no relevant interactions via the cytochrome P450 liver enzymes are expected. [4] [11]

Pharmacology

Mechanism of action

Hypophosphatasia is caused by a genetic defect of tissue-nonspecific alkaline phosphatase (TNSALP), an enzyme that plays a role in bone mineralization. Asfotase alfa is a recombinant glycoprotein that contains the catalytic domain (the active site) of TNSALP. It is thus a form of enzyme replacement therapy. [4] [11]

Pharmacokinetics

After subcutaneous injection, asfotase alfa has a bioavailability of 46–98% and reaches highest blood plasma concentrations after 24 to 48 hours. [11] Elimination half life is five days. [4]

Chemistry

The peptide part of the glycoprotein asfotase alfa consists of two identical chains of 726 amino acids each, containing (1) the catalytic domain of TNSALP, (2) the Fc region of human immunoglobulin G1, and (3) a sequence of ten L-aspartate residues at the carboxy terminus. The two chains are linked by two disulfide bridges. Each chain also contains four internal disulfide bridges. [4] [11]

The complete peptide sequence of one chain is [12] [13] 

LVPEKEKDPK YWRDQAQETL KYALELQKLN TNVAKNVIMF LGDGMGVSTV TAARILKGQL HHNPGEETRL EMDKFPFVAL SKTYNTNAQV PDSAGTATAY LCGVKANEGT VGVSAATERS RCNTTQGNEV TSILRWAKDA GKSVGIVTTT RVNHATPSAA YAHSADRDWY SDNEMPPEAL SQGCKDIAYQ LMHNIRDIDV IMGGGRKYMY PKNKTDVEYE SDEKARGTRL DGLDLVDTWK SFKPRYKHSH FIWNRTELLT LDPHNVDYLL GLFEPGDMQY ELNRNNVTDP SLSEMVVVAI QILRKNPKGF FLLVEGGRID HGHHEGKAKQ ALHEAVEMDR AIGQAGSLTS SEDTLTVVTA DHSHVFTFGG YTPRGNSIFG LAPMLSDTDK KPFTAILYGN GPGYKVVGGE RENVSMVDYA HNNYQAQSAV PLRHETHGGE DVAVFSKGPM AHLLHGVHEQ NYVPHVMAYA ACIGANLGHC APASSLKDKT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPGKDIDDDD DDDDDD

Asfotase alfa is produced in Chinese hamster ovary cells. [4] [11]

History

Asfotase alfa was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) in September 2008. [14]

Asfotase alfa is manufactured by Alexion Pharmaceuticals and it was granted breakthrough therapy designation by the U.S. FDA in 2015 as it is the first and only treatment for perinatal, infantile and juvenile-onset HPP. [6] [15] It was approved in October 2015, in the U.S. [16] [6] and in August 2015, in the EU. [5]

The safety and efficacy of asfotase alfa were established in 99 participants with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies. [6] Study results showed that participants with perinatal- and infantile-onset HPP treated with asfotase alfa had improved overall survival and survival without the need for a ventilator (ventilator-free survival). [6] Ninety-seven percent of treated participants were alive at one year of age compared to 42 percent of control participants selected from a natural history study group. [6] Similarly, the ventilator-free survival rate at one year of age was 85 percent for treated participants compared to less than 50 percent for the natural history control participants. [6]

Participants with juvenile-onset HPP treated with asfotase alfa showed improvements in growth and bone health compared to control participants selected from a natural history database. [6] All treated participants had improvement in low weight or short stature or maintained normal height and weight. [6] In comparison, approximately 20 percent of control participants had growth delays over time, with shifts in height or weight from the normal range for children their age to heights and weights well below normal for age. [6] Juvenile-onset participants also showed improvements in bone mineralization, as measured on a scale that evaluates the severity of rickets and other HPP-related skeletal abnormalities based on x-ray images. [6] All treated participants demonstrated substantial healing of rickets on x-rays while some natural history control participants showed increasing signs of rickets over time. [6]

Related Research Articles

<span class="mw-page-title-main">Gaucher's disease</span> Medical condition

Gaucher's disease or Gaucher disease (GD) is a genetic disorder in which glucocerebroside accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase, which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages. Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.

<span class="mw-page-title-main">Alkaline phosphatase</span> Homodimeric protein enzyme

The enzyme alkaline phosphatase has the physiological role of dephosphorylating compounds. The enzyme is found across a multitude of organisms, prokaryotes and eukaryotes alike, with the same general function but in different structural forms suitable to the environment they function in. Alkaline phosphatase is found in the periplasmic space of E. coli bacteria. This enzyme is heat stable and has its maximum activity at high pH. In humans, it is found in many forms depending on its origin within the body – it plays an integral role in metabolism within the liver and development within the skeleton. Due to its widespread prevalence in these areas, its concentration in the bloodstream is used by diagnosticians as a biomarker in helping determine diagnoses such as hepatitis or osteomalacia.

<span class="mw-page-title-main">Glycogen storage disease type II</span> Medical condition

Glycogen storage disease type II, also called Pompe disease, and formerly known as GSD-IIa. It is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. GSD-II and Danon disease are the only glycogen storage diseases with a defect in lysosomal metabolism, and Pompe disease was the first glycogen storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe.

Thomas Walter Warnes was an English gastroenterologist.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. MLD involves cerebroside sulfate accumulation. Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern.

<span class="mw-page-title-main">Hypophosphatasia</span> Medical condition

Hypophosphatasia (; also called deficiency of alkaline phosphatase, phosphoethanolaminuria, or Rathbun's syndrome; sometimes abbreviated HPP) is a rare, and sometimes fatal, inherited metabolic bone disease. Clinical symptoms are heterogeneous, ranging from the rapidly fatal, perinatal variant, with profound skeletal hypomineralization, respiratory compromise or vitamin B6 dependent seizures to a milder, progressive osteomalacia later in life. Tissue non-specific alkaline phosphatase (TNSALP) deficiency in osteoblasts and chondrocytes impairs bone mineralization, leading to rickets or osteomalacia. The pathognomonic finding is subnormal serum activity of the TNSALP enzyme, which is caused by one of 388 genetic mutations identified to date, in the gene encoding TNSALP. Genetic inheritance is autosomal recessive for the perinatal and infantile forms but either autosomal recessive or autosomal dominant in the milder forms.

A lipid storage disorder is any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some body cells and tissues. People with these disorders either do not produce enough of one of the enzymes needed to metabolize and break down lipids or, they produce enzymes that do not work properly. Over time, the buildup of fats may cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen, and bone marrow.

<span class="mw-page-title-main">Miglustat</span> Medication

Miglustat, sold under the brand name Zavesca among others, is a medication used to treat type I Gaucher disease and Pompe disease.

Alglucosidase alfa, sold under the brand name Myozyme among others, is an enzyme replacement therapy (ERT) orphan drug for treatment of Pompe disease, a rare lysosomal storage disorder (LSD). Chemically, the drug is an analog of the enzyme that is deficient in patients affected by Pompe disease, alpha-glucosidase. It is the first drug available to treat this disease.

<span class="mw-page-title-main">ALPL</span> Protein-coding gene in the species Homo sapiens

Alkaline phosphatase, tissue-nonspecific isozyme is an enzyme that in humans is encoded by the ALPL gene.

Radium-223 is an isotope of radium with an 11.4-day half-life. It was discovered in 1905 by T. Godlewski, a Polish chemist from Kraków, and was historically known as actinium X (AcX). Radium-223 dichloride is an alpha particle-emitting radiotherapy drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover. The principal use of radium-223, as a radiopharmaceutical to treat metastatic cancers in bone, takes advantage of its chemical similarity to calcium, and the short range of the alpha radiation it emits.

<span class="mw-page-title-main">Elevated alkaline phosphatase</span> Medical condition

Elevated alkaline phosphatase occurs when levels of alkaline phosphatase (ALP) exceed the reference range. This group of enzymes has a low substrate specificity and catalyzes the hydrolysis of phosphate esters in a basic environment. The major function of alkaline phosphatase is transporting chemicals across cell membranes. Alkaline phosphatases are present in many human tissues, including bone, intestine, kidney, liver, placenta and white blood cells. Damage to these tissues causes the release of ALP into the bloodstream. Elevated levels can be detected through a blood test. Elevated alkaline phosphate is associated with certain medical conditions or syndromes. It serves as a significant indicator for certain medical conditions, diseases and syndromes.

Velaglucerase alfa, sold under the brand name Vpriv, is a medication used for the treatment of Gaucher disease Type 1. It is a hydrolytic lysosomal glucocerebroside-specific enzyme, which is a recombinant form of glucocerebrosidase. It has an identical amino acid sequence to the naturally occurring enzyme. It is manufactured by Shire plc.

Alexion Pharmaceuticals, a subsidiary of AstraZeneca, is a pharmaceutical company headquartered in Boston, Massachusetts that specializes in orphan drugs to treat rare diseases.

Burosumab, sold under the brand name Crysvita, is a human monoclonal antibody medication approved 2018 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia.

Cerliponase alfa, marketed as Brineura, is an enzyme replacement treatment for Batten disease, a neurodegenerative lysosomal storage disease. Specifically, Cerliponase alfa is meant to slow loss of motor function in symptomatic children over three years old with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). The disease is also known as tripeptidyl peptidase-1 (TPP1) deficiency, a soluble lysosomal enzyme deficiency. Approved by the United States Food and Drug Administration (FDA) on 27 April 2017, this is the first treatment for a neuronal ceroid lipofuscinosis of its kind, acting to slow disease progression rather than palliatively treat symptoms by giving patients the TPP1 enzyme they are lacking.

Vestronidase alfa, sold under brand name Mepsevii, is a drug for the treatment of Sly syndrome. It is a recombinant form of the human enzyme beta-glucuronidase. It was approved in the United States in November 2017, to treat children and adults with an inherited metabolic condition called mucopolysaccharidosis type VII, also known as Sly syndrome. MPS VII is an extremely rare, progressive condition that affects most tissues and organs.

Lumasiran, sold under the brand name Oxlumo, is a medication for the treatment of primary hyperoxaluria type 1 (PH1).

Avalglucosidase alfa, sold under the brand name Nexviazyme, is an enzyme replacement therapy medication used for the treatment of glycogen storage disease type II.

Olipudase alfa, sold under the brand name Xenpozyme, is a medication used for the treatment of non-central nervous system (CNS) manifestations of acid sphingomyelinase deficiency (ASMD) type A/B or type B.

References

  1. ↑ "Asfotase alfa (Strensiq) Use During Pregnancy". Drugs.com. 15 July 2019. Retrieved 10 May 2020.
  2. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  3. ↑ "Strensiq - Summary of Product Characteristics (SmPC)". (emc). 21 January 2020. Retrieved 10 May 2020.
  4. 1 2 3 4 5 6 7 8 9 "Strensiq- asfotase alfa solution". DailyMed. 7 February 2018. Retrieved 10 May 2020.
  5. 1 2 3 4 5 6 "Strensiq EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 10 May 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 "FDA approves new treatment for rare metabolic disorder". U.S. Food and Drug Administration (FDA) (Press release). 24 October 2015. Archived from the original on 24 October 2015. Retrieved 11 May 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. ↑ U.S. Patent 7,763,712.
  8. ↑ Scott LJ (February 2016). "Asfotase Alfa: A Review in Paediatric-Onset Hypophosphatasia". Drugs. 76 (2): 255–62. doi:10.1007/s40265-015-0535-2. PMID   26744272. S2CID   23910180.
  9. ↑ Hofmann C, Seefried L, Jakob F (May 2016). "Asfotase alfa: enzyme replacement for the treatment of bone disease in hypophosphatasia". Drugs of Today. Barcelona, Spain. 52 (5): 271–85. doi:10.1358/dot.2016.52.5.2482878. PMID   27376160.
  10. ↑ Bowden SA, Foster BL (2018). "Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy". Drug Design, Development and Therapy. 12: 3147–3161. doi: 10.2147/DDDT.S154922 . PMC   6161731 . PMID   30288020.
  11. 1 2 3 4 5 6 Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Strensiq Injektionslösung.
  12. ↑ DrugBank: Asfotase Alfa.
  13. ↑ KEGG: Asfotase Alfa
  14. ↑ "Asfotase alfa Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 10 May 2020.
  15. ↑ CDER Breakthrough Therapy Designation Approvals.
  16. ↑ "Strensiq (asfotase alfa) solution for subcutaneous injection". U.S. Food and Drug Administration (FDA). 3 December 2015. Retrieved 10 May 2020.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.