Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of

achondroplasia Achondroplasia is a genetic disorder with an autosomal dominant pattern of inheritance whose primary feature is dwarfism. It is the most common cause of dwarfism and affects about 1 in 27,500 people. In those with the condition, the Rhizomeli ...

, a genetic condition that causes severely short stature and disproportionate growth. Achondroplasia is caused by a genetic mutation that increases the activity of a certain growth regulation

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

called

fibroblast growth factor receptor 3 Fibroblast growth factor receptor 3 (FGFR-3) is a protein that in humans is encoded by the ''FGFR3'' gene. FGFR3 has also been designated as CD333 (cluster of differentiation 333). The gene, which is located on chromosome 4, location p16.3, is e ...

(''FGFR3''). The overabundance of protein coded by the ''FGFR3'' gene prevents normal bone growth. Vosoritide works by binding to a specific receptor called natriuretic peptide receptor B that reduces the growth regulation gene's activity, thus allowing for bone growth. The most common side effects include injection site reactions (such as swelling, redness, itching, or pain), vomiting, and decreased blood pressure. Vosoritide was approved for medical use in the European Union in August 2021, and in the United States in November 2021. The US

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 respo ...

considers it to be a

first-in-class medication A first-in-class medication is a prototype drug that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medic ...

Medical uses

In the European Union, vosoritide 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 achondroplasia in people two years of age and older whose

epiphyses An epiphysis (; : epiphyses) is one of the rounded ends or tips of a long bone that ossify from one or more secondary centers of ossification. Between the epiphysis and diaphysis (the long midsection of the long bone) lies the metaphysis, inc ...

are not closed. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. In the United States, vosoritide is indicated to increase growth in children five years of age and older with achondroplasia and open epiphyses (growth plates).

Mechanism of action

Vosoritide works by binding to a receptor (target) called natriuretic peptide receptor type B (NPR-B), which reduces the activity of

(FGFR3). FGFR3 is a

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

that normally down-regulates

cartilage Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...

and bone growth when activated by one of the proteins known as

acidic An acid is a molecule or ion capable of either donating a proton (i.e. hydrogen cation, H+), known as a Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis acid. The first category of acids are the ...

and

basic fibroblast growth factor Fibroblast growth factor 2 (FGF-2), also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor recept ...

. It does so by inhibiting the development (

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...

and differentiation) of

chondrocyte Chondrocytes (, ) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word '' chondroblast'' is commonly used to describe an immatu ...

s, the cells that produce and maintain the cartilaginous matrix which is also necessary for bone growth. Children with achondroplasia have one of several possible FGFR3 mutations resulting in constitutive (permanent) activity of this receptor, resulting in overall reduced chondrocyte activity and thus bone growth. The protein

C-type natriuretic peptide Natriuretic peptide precursor C, also known as NPPC, is a protein that in humans is encoded by the ''NPPC'' gene. The precursor NPPC protein is cleaved to the 22 amino acid peptide C-type natriuretic peptide (''CNP''). Function Natriuretic ...

(CNP), naturally found in humans, reduces the effects of over-active FGFR3. Vosoritide is a CNP analogue with the same effect but prolonged half-life, allowing for once-daily administration.

Chemistry

Vosoritide is an

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analog ...

of CNP. It is a

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

consisting of the amino acids

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

and

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

plus the 37

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

amino acids from natural human CNP. The complete

peptide sequence Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ami ...

is : P G Q E H P N A R K YKGANKKG L S KG C FGLKL DR IGS MSGLGC with a

disulfide bridge In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inorg ...

between positions 23 and 39 (underlined). The drug must be administered by injection as it would be rendered ineffective by the digestive system if taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

History

Vosoritide was developed by

BioMarin Pharmaceutical BioMarin Pharmaceutical Inc. is an American biotechnology company headquartered in San Rafael, California. It has offices and facilities in the United States, South America, Asia, and Europe. BioMarin's core business and research is in enzyme re ...

and got

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

status in the US as well as the European Union. The safety and efficacy of vosoritide in improving growth were evaluated in a year-long, double-blind, placebo-controlled, phase III study in participants five years and older with achondroplasia who have open epiphyses. In the study, 121 participants were randomly assigned to receive either vosoritide injections under the skin or a placebo. Researchers measured the participants' annualized growth velocity, or rate of height growth, at the end of the year. Participants who received vosoritide grew an average 1.57 centimeters taller compared to those who received a placebo. The US

(FDA) granted the approval of Voxzogo to BioMarin.

Society and culture

Controversy

Little People of America, a national nonprofit organization that provides support and information to people of short stature and their families, states "LPA strongly believes that a pharmaceutical intervention focusing on growth velocity is not addressing the actual health and quality of life issues of people with dwarfism. Our height-related challenges are primarily based on inaccessible architecture, lack of universal design, and society’s intolerance and discrimination of people with short stature. We are concerned that this recently approved drug attempts a pharmaceutical solution to a societal issue. Our community acknowledges that the hardships associated with having dwarfism need to be addressed. Yet, we strive for our height to be reframed as a part of the diversity of humanity. We want to reprioritize research goals to be the most meaningful ones for our members, such as reducing spinal stenosis, sleep apnea, and the need for corrective surgeries."

Research

Vosoritide has resulted in increased growth in a clinical trial with 26 children. The ten children receiving the highest dose grew in six months, compared to in the six months before the treatment ( p=0.01). The

body proportions Body proportions is the study of artistic anatomy, which attempts to explore the relation of the elements of the human body to each other and to the whole. These ratios are used in depictions of the human figure and may become part of an artisti ...

, more specifically the ratio of leg length to upper body length – which is lower in achondroplasia patients than in the average population – was not improved by vosoritide, but not worsened either.

References

External links

* {{Portal bar, Medicine Orphan drugs Dwarfism