Asfotase alfa

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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. [5] [6] [7] [8] [9] [10] [11]

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. [7] [6]

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. [6]

Medical uses

In the United States, asfotase alfa is indicated for the treatment of people with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP). [5]

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. [6]

Adverse effects

The most common adverse effects in studies included injection site reactions (pain, itching, erythema, etc.), headache, limb pain, and haematoma. [5] [6] Possible rare side effects could not be assessed because of the low number of patients. [12] [5]

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. [5] [12]

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. [5] [12]

Pharmacokinetics

After subcutaneous injection, asfotase alfa has a bioavailability of 46–98% and reaches highest blood plasma concentrations after 24 to 48 hours. [12] Elimination half life is five days. [5]

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. [5] [12]

The complete peptide sequence of one chain is [13] [14] 

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. [5] [12]

History

Asfotase alfa was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) in September 2008. [15]

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. [7] [16] It was approved in October 2015, in the U.S. [17] [7] and in August 2015, in the EU. [6]

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. [7] 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). [7] 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. [7] 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. [7]

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. [7] All treated participants had improvement in low weight or short stature or maintained normal height and weight. [7] 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. [7] 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. [7] All treated participants demonstrated substantial healing of rickets on x-rays while some natural history control participants showed increasing signs of rickets over time. [7]

Related Research Articles

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

The enzyme alkaline phosphatase is a phosphatase with 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(GSD-II), also called Pompe disease, and formerly known as GSD-IIa or LGMD2V, 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 (GAA). The inability to breakdown glycogen within the lysosomes of cells leads to progressive muscle weakness throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and the nervous system.

Batten disease is a fatal disease of the nervous system that typically begins in childhood. Onset of symptoms is usually between 5 and 10 years of age. Often, it is autosomal recessive. It is the common name for a group of disorders called the neuronal ceroid lipofuscinoses (NCLs).

<span class="mw-page-title-main">Neuronal ceroid lipofuscinosis</span> Medical condition

Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.

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">X-linked hypophosphatemia</span> X-linked dominant disorder that causes rickets

X-linked hypophosphatemia (XLH) is an X-linked dominant form of rickets that differs from most cases of dietary deficiency rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short stature and genu varum (bow-leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. PHEX mutations lead to an elevated circulating (systemic) level of the hormone FGF23 which results in renal phosphate wasting, and local elevations of the mineralization/calcification-inhibiting protein osteopontin in the extracellular matrix of bones and teeth. An inactivating mutation in the PHEX gene results in an increase in systemic circulating FGF23, and a decrease in the enzymatic activity of the PHEX enzyme which normally removes (degrades) mineralization-inhibiting osteopontin protein; in XLH, the decreased PHEX enzyme activity leads to an accumulation of inhibitory osteopontin locally in bones and teeth to block mineralization which, along with renal phosphate wasting, both cause osteomalacia and odontomalacia.

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

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

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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.

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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. ↑ "Health Canada New Drug Authorizations: 2015 Highlights". Health Canada . 4 May 2016. Retrieved 7 April 2024.
  4. ↑ "Strensiq - Summary of Product Characteristics (SmPC)". (emc). 21 January 2020. Retrieved 10 May 2020.
  5. 1 2 3 4 5 6 7 8 9 "Strensiq- asfotase alfa solution". DailyMed. 7 February 2018. Retrieved 10 May 2020.
  6. 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.
  7. 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 .
  8. ↑ U.S. Patent 7,763,712.
  9. ↑ 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.
  10. ↑ Hofmann C, Seefried L, Jakob F (May 2016). "Asfotase alfa: enzyme replacement for the treatment of bone disease in hypophosphatasia". Drugs of Today. 52 (5). Barcelona, Spain: 271–85. doi:10.1358/dot.2016.52.5.2482878. PMID   27376160.
  11. ↑ 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.
  12. 1 2 3 4 5 6 Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Strensiq Injektionslösung.
  13. ↑ DrugBank: Asfotase Alfa.
  14. ↑ KEGG: Asfotase Alfa
  15. ↑ "Asfotase alfa Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 10 May 2020.
  16. ↑ CDER Breakthrough Therapy Designation Approvals.
  17. ↑ "Strensiq (asfotase alfa) solution for subcutaneous injection". U.S. Food and Drug Administration (FDA). 3 December 2015. Retrieved 10 May 2020.
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