Vosoritide

Last updated
Vosoritide
Vosoritid.svg
Clinical data
Trade names Voxzogo
Other namesBMN-111
License data
Pregnancy
category
Routes of
administration 		Subcutaneous injection
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C176H290N56O51S3
Molar mass 4102.78 g·mol−1
3D model (JSmol)
  • CC[C@H](C)[C@H]1C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)CCCNC(=N)N)CC(=O)O)CC(C)C)CCCCN)CC(C)C)Cc2ccccc2)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc3ccc(cc3)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)N)NC(=O)[C@@H]4CCCN4C(=O)[C@H](Cc5cnc[nH]5)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)CNC(=O)[C@@H]6CCCN6)C(=O)O)CC(C)C)CO)CCSC)CO
  • InChI=1S/C176H290N56O51S3/c1-14-95(10)143-172(280)201-84-138(245)209-125(86-234)168(276)221-113(54-65-284-13)159(267)229-124(85-233)152(260)200-81-135(242)206-114(66-91(2)3)150(258)198-83-140(247)211-128(174(282)283)89-286-285-88-127(170(278)224-118(70-98-34-16-15-17-35-98)151(259)199-80-137(244)207-115(67-92(4)5)162(270)217-108(41-23-29-60-182)155(263)223-117(69-94(8)9)164(272)226-122(75-142(250)251)167(275)219-110(160(268)231-143)44-32-63-193-176(188)189)210-139(246)82-197-149(257)105(38-20-26-57-179)215-169(277)126(87-235)230-163(271)116(68-93(6)7)208-136(243)79-196-147(255)103(36-18-24-55-177)213-153(261)106(39-21-27-58-180)218-166(274)121(74-132(185)239)222-144(252)96(11)203-133(240)77-195-148(256)104(37-19-25-56-178)214-165(273)119(71-99-46-48-101(236)49-47-99)225-156(264)107(40-22-28-59-181)216-154(262)109(43-31-62-192-175(186)187)212-145(253)97(12)204-161(269)120(73-131(184)238)227-171(279)129-45-33-64-232(129)173(281)123(72-100-76-190-90-202-100)228-158(266)112(51-53-141(248)249)220-157(265)111(50-52-130(183)237)205-134(241)78-194-146(254)102-42-30-61-191-102/h15-17,34-35,46-49,76,90-97,102-129,143,191,233-236H,14,18-33,36-45,50-75,77-89,177-182H2,1-13H3,(H2,183,237)(H2,184,238)(H2,185,239)(H,190,202)(H,194,254)(H,195,256)(H,196,255)(H,197,257)(H,198,258)(H,199,259)(H,200,260)(H,201,280)(H,203,240)(H,204,269)(H,205,241)(H,206,242)(H,207,244)(H,208,243)(H,209,245)(H,210,246)(H,211,247)(H,212,253)(H,213,261)(H,214,273)(H,215,277)(H,216,262)(H,217,270)(H,218,274)(H,219,275)(H,220,265)(H,221,276)(H,222,252)(H,223,263)(H,224,278)(H,225,264)(H,226,272)(H,227,279)(H,228,266)(H,229,267)(H,230,271)(H,231,268)(H,248,249)(H,250,251)(H,282,283)(H4,186,187,192)(H4,188,189,193)/t95-,96-,97-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,143-/m0/s1
  • Key:IGYWDDBBJPSOTG-WBAGYEQSSA-N

Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of achondroplasia, [3] [4] [5] a genetic condition that causes severely short stature and disproportionate growth. [4]

Contents

Achondroplasia is caused by a genetic mutation that increases the activity of a certain growth regulation gene called fibroblast growth factor receptor 3 (FGFR3). The overabundance of protein coded by the FGFR3 gene prevents normal bone growth. [4] 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. [4]

The most common side effects include injection site reactions (such as swelling, redness, itching, or pain), vomiting, and decreased blood pressure. [3] [4] [5]

Vosoritide was approved for medical use in the European Union in August 2021, [5] [6] [7] and in the United States in November 2021. [4] [8] The US Food and Drug Administration considers it to be a first-in-class medication. [9]

Medical uses

In the European Union, vosoritide is indicated for the treatment of achondroplasia in people two years of age and older whose epiphyses are not closed. [5]

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). [3] [4]

Mechanism of action

A: Chondrocyte with constitutionally active FGFR3 that down-regulates its development via the MAPK/ERK pathway B: Vosoritide (BMN 111) blocks this mechanism by binding to the atrial natriuretic peptide receptor B (NPR-B), which subsequently inhibits the MAPK/ERK pathway at the RAF-1 protein. Vosoritide mechanism.png
A: Chondrocyte with constitutionally active FGFR3 that down-regulates its development via the MAPK/ERK pathway
B: Vosoritide (BMN 111) blocks this mechanism by binding to the atrial natriuretic peptide receptor B (NPR-B), which subsequently inhibits the MAPK/ERK pathway at the RAF-1 protein.

Vosoritide works by binding to a receptor (target) called natriuretic peptide receptor type B (NPR-B), which reduces the activity of fibroblast growth factor receptor 3 (FGFR3). [5] FGFR3 is a receptor that normally down-regulates cartilage and bone growth when activated by one of the proteins known as acidic and basic fibroblast growth factor. It does so by inhibiting the development (cell proliferation and differentiation) of chondrocytes, 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. [10]

The protein C-type natriuretic peptide (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, [10] allowing for once-daily administration. [11]

Chemistry

Vosoritide is an analog of CNP. It is a peptide consisting of the amino acids proline and glycine plus the 37 C-terminal amino acids from natural human CNP. The complete peptide sequence is

P G Q E H P N A R K YKGANKKGL S KG C FGLKLDR IGSMSGLGC

with a disulfide bridge between positions 23 and 39 (underlined). [12] The drug must be administered by injection as it would be rendered ineffective by the digestive system if taken by mouth.

History

Vosoritide was developed by BioMarin Pharmaceutical and got orphan drug status in the US as well as the European Union. [5] [7] [13] [9]

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. [4] In the study, 121 participants were randomly assigned to receive either vosoritide injections under the skin or a placebo. [4] Researchers measured the participants' annualized growth velocity, or rate of height growth, at the end of the year. [4] Participants who received vosoritide grew an average 1.57 centimeters taller compared to those who received a placebo. [4] The US Food and Drug Administration (FDA) granted the approval of Voxzogo to BioMarin. [4]

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." [14]

Research

Vosoritide has resulted in increased growth in a clinical trial with 26 children. The ten children receiving the highest dose grew 6.1 centimetres (2.4 in) in six months, compared to 4.0 centimetres (1.6 in) in the six months before the treatment (p=0.01). [15] The body proportions, 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. [16] > [17]

Related Research Articles

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 arms and legs are short, while the torso is typically of normal length. Those affected have an average adult height of 131 centimetres for males and 123 centimetres (4 ft) for females. Other features can include an enlarged head with prominent forehead and underdevelopment of the midface. Complications can include sleep apnea or recurrent ear infections. Achondroplasia includes the extremely rare short-limb skeletal dysplasia with severe combined immunodeficiency.

<span class="mw-page-title-main">Atrial natriuretic peptide</span> Cardiac hormone which increases renal sodium excretion

Atrial Natriuretic Peptide (ANP) or atrial natriuretic factor (ANF) is a natriuretic peptide hormone secreted from the cardiac atria that in humans is encoded by the NPPA gene. Natriuretic peptides are a family of hormone/paracrine factors that are structurally related. The main function of ANP is causing a reduction in expanded extracellular fluid (ECF) volume by increasing renal sodium excretion. ANP is synthesized and secreted by cardiac muscle cells in the walls of the atria in the heart. These cells contain volume receptors which respond to increased stretching of the atrial wall due to increased atrial blood volume.

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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 replacement therapies (ERTs). BioMarin was the first company to provide therapeutics for mucopolysaccharidosis type I, by manufacturing laronidase. BioMarin was also the first company to provide therapeutics for phenylketonuria (PKU).

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<span class="mw-page-title-main">Natriuretic peptide</span> Hormone used in regulating the cardiovascular system

A natriuretic peptide is a hormone molecule that plays a crucial role in the regulation of the cardiovascular system. These hormones were first discovered in the 1980s and were found to have very strong diuretic, natriuretic, and vasodilatory effects. There are three main types of natriuretic peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Two minor hormones include Urodilatin (URO) which is processed in the kidney and encoded by the same gene as ANP, and Dendroaspis NP (DNP) that was discovered through isolation of the venom from the green mamba snake. Since they are activated during heart failure, they are important for the protection of the heart and its tissues.

<span class="mw-page-title-main">Fibroblast growth factor receptor 3</span> Gene involved in the most common form of dwarfism

Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene. FGFR3 has also been designated as CD333. The gene, which is located on chromosome 4, location p16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys.

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<span class="mw-page-title-main">Severe achondroplasia with developmental delay and acanthosis nigricans</span> Medical condition

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is a very rare genetic disorder. This disorder is one that affects bone growth and is characterized by skeletal, brain, and skin abnormalities. Those affected by the disorder are severely short in height and commonly possess shorter arms and legs. In addition, the bones of the legs are often bowed and the affected have smaller chests with shorter rib bones, along with curved collarbones. Other symptoms of the disorder include broad fingers and extra folds of skin on the arms and legs. Developmentally, many individuals who suffer from the disorder show a higher level in delays and disability. Seizures are also common due to structural abnormalities of the brain. Those affected may also suffer with apnea, the slowing or loss of breath for short periods of time.

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References

  1. 1 2 "Voxzogo APMDS". Therapeutic Goods Administration (TGA). 4 August 2022. Archived from the original on 6 August 2022. Retrieved 6 August 2022.
  2. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
  3. 1 2 3 4 "Voxzogo 0.4MG- vosoritide kit Voxzogo 0.56MG- vosoritide kit Voxzogo 1.2MG- vosoritide kit". DailyMed. Archived from the original on 19 December 2021. Retrieved 19 December 2021.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 "FDA Approves First Drug to Improve Growth in Children with Most Common Form of Dwarfism". U.S. Food and Drug Administration (FDA) (Press release). 19 November 2021. Archived from the original on 19 November 2021. Retrieved 19 November 2021.PD-icon.svg This article incorporates text from this source, which is in the public domain.
  5. 1 2 3 4 5 6 7 "Voxzogo EPAR". European Medicines Agency. 23 June 2021. Archived from the original on 10 September 2021. Retrieved 9 September 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ↑ "Voxzogo Product information". Union Register of medicinal products. Archived from the original on 4 March 2023. Retrieved 3 March 2023.
  7. 1 2 "European Commission Approves BioMarin's Voxzogo (vosoritide) for the Treatment of Children with Achondroplasia from Age 2 Until Growth Plates Close" (Press release). BioMarin Pharmaceutical. 27 August 2021. Archived from the original on 28 August 2021. Retrieved 9 September 2021– via PR Newswire.
  8. ↑ "BioMarin Receives FDA Approval for Voxzogo (vosoritide) for Injection, Indicated to Increase Linear Growth in Children with Achondroplasia Aged 5 and Up with Open Growth Plates" (Press release). BioMarin Pharmaceutical. 19 November 2021. Archived from the original on 6 August 2022. Retrieved 19 November 2021– via PR Newswire.
  9. 1 2 Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. 1 2 3 Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, et al. (December 2012). "Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia". American Journal of Human Genetics. 91 (6): 1108–14. doi:10.1016/j.ajhg.2012.10.014. PMC   3516592 . PMID   23200862.
  11. ↑ Clinical trial number NCT02055157 for "A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia (ACH)" at ClinicalTrials.gov
  12. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN): List 112" (PDF). WHO Drug Information. 28 (4): 539. 2014.
  13. ↑ "Food and Drug Administration Accepts BioMarin's New Drug Application for Vosoritide to Treat Children with Achondroplasia" (Press release). BioMarin Pharmaceutical. 2 November 2020. Archived from the original on 10 September 2021. Retrieved 9 September 2021– via PR Newswire.
  14. ↑ "Archived copy". Archived from the original on 2024-02-15. Retrieved 2024-03-10.{{cite web}}: CS1 maint: archived copy as title (link)
  15. ↑ "BMN 111 (vosoritide) Improves Growth Velocity in Children With Achondroplasia in Phase 2 Study". BioMarin. 17 June 2015. Archived from the original on 9 September 2015. Retrieved 12 September 2015.
  16. ↑ Spreitzer H (6 July 2015). "Neue Wirkstoffe – Vosoritid". Österreichische Apothekerzeitung (in German) (14/2015): 28.
  17. ↑ "Vosoritid" (in German). Arznei-News.de. 20 June 2015. Archived from the original on 6 March 2016. Retrieved 10 September 2015.
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