Asfotase alfa, sold under the brand name Strensiq, is a medication used in the treatment of people with

perinatal Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...

/infantile- and juvenile-onset

hypophosphatasia 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, ...

. U.S. Patent 7,763,712
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. 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.

Medical uses

In the United States, asfotase alfa is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of people with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP). 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.

Adverse effects

The most common adverse effects in studies included injection site reactions (pain, itching,

erythema Erythema (from the Greek , meaning red) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not asso ...

, etc.), headache, limb pain, and haematoma. Possible rare side effects could not be assessed because of the low number of patients.

Interactions

Asfotase alfa interferes with alkaline phosphatase measurements. As asfotase alfa is a glycoprotein (as opposed to a

small molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...

), no relevant interactions via the

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

liver enzymes are expected.

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 Biomineralization, also written biomineralisation, is the process by which living organisms produce minerals, often to harden or stiffen existing tissues. Such tissues are called mineralized tissues. It is an extremely widespread phenomenon; ...

. Asfotase alfa is a recombinant glycoprotein that contains the

catalytic domain In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...

(the active site) of TNSALP. It is thus a form of

enzyme replacement therapy Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme. ERT is availa ...

Pharmacokinetics

After subcutaneous injection, asfotase alfa has a

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of 46–98% and reaches highest blood plasma concentrations after 24 to 48 hours. Elimination half life is five days.

Chemistry

The

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

part of the glycoprotein asfotase alfa consists of two identical chains of 726

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

s each, containing (1) the catalytic domain of TNSALP, (2) the

Fc region The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune s ...

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 bridge In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

s. Each chain also contains four internal disulfide bridges. The complete peptide sequence of one chain is 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 cell Chinese hamster ovary (CHO) cells are an epithelial cell line derived from the ovary of the Chinese hamster, often used in biological and medical research and commercially in the production of recombinant therapeutic proteins. They have found wide ...

History

Asfotase alfa was granted orphan drug designation by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) in September 2008. Asfotase alfa is manufactured by

Alexion Pharmaceuticals Alexion Pharmaceuticals is an American pharmaceutical company headquartered in Boston, Massachusetts that specializes in orphan drugs to treat rare diseases. It became an independent subsidiary of AstraZeneca in 2021. Its products include ecul ...

and it was granted

breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...

designation by the U.S. FDA in 2015 as it is the first and only treatment for perinatal, infantile and juvenile-onset HPP.CDER Breakthrough Therapy Designation Approvals
It was approved in October 2015, in the U.S. and in August 2015, in the EU. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. 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. 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). 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. 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. 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. All treated participants had improvement in low weight or short stature or maintained normal height and weight. 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. 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. All treated participants demonstrated substantial healing of rickets on x-rays while some natural history control participants showed increasing signs of rickets over time.

References

External links

* {{Portal bar , Medicine AstraZeneca brands Breakthrough therapy Recombinant proteins Hydrolases Orphan drugs