Asfotase alfa

Asfotase alfa
Names
Trade namesStrensiq
Other namesALXN-1215
Clinical data
Drug classEnzyme[1]
Main usesHypophosphatasia (HPP)[2]
Side effectsHeadache, redness of the skin, pain in the limbs, fever, lipodystrophy, allergic reactions, bruising at the site of injection[1][2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: C[3]
  • US: N (Not classified yet)[3]
    Routes of
    use    		Subcutaneous injection
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only) [4]
    • US: ℞-only
    • EU: Rx-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability46–98%
    Elimination half-life~5 days
    Chemical and physical data
    FormulaC7108H11008N1968O2206S56
    Molar mass161125.18 g·mol−1

    Asfotase alfa, sold under the brand name Strensiq, is a medication used to treat hypophosphatasia (HPP) that starts in children.[2][1] It is given by injection under the skin.[2]

    Common side effects include headache, redness of the skin, pain in the limbs, fever, lipodystrophy, allergic reactions, and bruising at the site of injection.[1][2] Other side effects may include calcification of the eyes or kidneys.[2] Safety in pregnancy is unclear.[3] It is a tissue non-specific alkaline phosphatase (ALP) and it works by replacing this enzyme in those affected.[2]

    Asfotase alfa was approved for medical use in the United States and Europe in 2015.[1] In the United Kingdom 4 weeks at a dose of 80 mg costs the NHS about £56,500 as of 2021.[5] This amount in the United States costs about 70,200 USD.[6]

    Medical uses

    In the United States, asfotase alfa is indicated for the treatment of people with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP).[2]

    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.[1]

    Dosage

    It is generally used at a dose of 2 mg/kg given three times per week.[2]

    Side effects

    The most common side effects included injection site reactions (pain, itching, erythema, etc.), headache, limb pain, and haematoma.[2][1] Possible rare side effects could not be assessed because of the low number of patients.[7][2]

    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.[2][7]

    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.[2][7]

    Pharmacokinetics

    After subcutaneous injection, asfotase alfa has a bioavailability of 46–98% and reaches highest blood plasma concentrations after 24 to 48 hours.[7] Elimination half life is five days.[2]

    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.[2][7]

    The complete peptide sequence of one chain is[8][9]

    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.[2][7]

    History

    Asfotase alfa was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) in September 2008.[10]

    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.[11][12] It was approved in October 2015, in the U.S.[13][11] and in August 2015, in the EU.[1]

    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.[11] 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).[11] 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.[11] 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.[11]

    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.[11] All treated participants had improvement in low weight or short stature or maintained normal height and weight.[11] 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.[11] 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.[11] All treated participants demonstrated substantial healing of rickets on x-rays while some natural history control participants showed increasing signs of rickets over time.[11]

    References

    1. 1 2 3 4 5 6 7 8 "Strensiq EPAR". European Medicines Agency (EMA). Archived from the original on 29 December 2019. Retrieved 10 May 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "Strensiq- asfotase alfa solution". DailyMed. 7 February 2018. Archived from the original on 24 March 2021. Retrieved 10 May 2020.
    3. 1 2 3 "Asfotase alfa (Strensiq) Use During Pregnancy". Drugs.com. 15 July 2019. Archived from the original on 31 October 2020. Retrieved 10 May 2020.
    4. ↑ "Strensiq - Summary of Product Characteristics (SmPC)". (emc). 21 January 2020. Archived from the original on 14 July 2017. Retrieved 10 May 2020.
    5. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1115. ISBN 978-0857114105.
    6. ↑ "Strensiq Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 14 May 2021. Retrieved 16 January 2022.
    7. 1 2 3 4 5 6 Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Strensiq Injektionslösung.{{cite book}}: CS1 maint: unrecognized language (link)
    8. ↑ DrugBank: Asfotase Alfa Archived 2016-11-08 at the Wayback Machine.
    9. ↑ KEGG: Asfotase Alfa Archived 2020-09-27 at the Wayback Machine
    10. ↑ "Asfotase alfa Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 24 December 1999. Archived from the original on 5 November 2021. Retrieved 10 May 2020.
    11. 1 2 3 4 5 6 7 8 9 10 11 "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. Public Domain This article incorporates text from this source, which is in the public domain.
    12. ↑ CDER Breakthrough Therapy Designation Approvals Archived 2019-02-08 at the Wayback Machine.
    13. ↑ "Strensiq (asfotase alfa) solution for subcutaneous injection". U.S. Food and Drug Administration (FDA). 3 December 2015. Archived from the original on 4 April 2021. Retrieved 10 May 2020.
    Identifiers:
    • "Asfotase alfa". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-11-05. Retrieved 2021-02-14.
    This article is issued from Offline. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.