| Size | Price | |
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| 500mg | ||
| 1g | ||
| Other Sizes |
Vosoritide (BMN-111; Voxzogo) is a peptide-based C-type natriuretic peptide (CNP) analogue approved in 2021 for the treatment of childhood achondroplasia. Vosoritide acts 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). 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: PGQEHPNARK YKGANKKGLS KGCFGLKLDR IGSMSGLGC.
Vosoritide, commercially known as VOXZOGO®, is a synthetic analog of human C-type natriuretic peptide (CNP) developed by BioMarin Pharmaceutical for treating achondroplasia. This condition arises from a gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3), which suppresses bone growth. Vosoritide promotes chondrogenesis by binding to natriuretic peptide receptor B (NPR-B), thereby inhibiting the downstream signaling pathways triggered by the overactive FGFR3 gene. In August 2021, the European Union approved vosoritide for patients aged two years and older with open epiphyses, requiring confirmation of achondroplasia through appropriate genetic testing. The drug is currently under regulatory review in the United States for the same indication, with clinical trials ongoing in multiple other countries. This article outlines the key developmental milestones that led to this initial approval for treating achondroplasia in this specific patient population.| Targets |
Natriuretic peptide receptor 2 (NPR2, also known as guanylyl cyclase B). Vosoritide (BMN-111) acts as an agonist of NPR2, stimulating the production of cyclic GMP (cGMP). [2]
The mechanism involves antagonizing fibroblast growth factor receptor 3 (FGFR3) downstream signaling by inhibiting the mitogen-activated protein kinase (MAPK) pathway, specifically reducing the phosphorylation of ERK1/2. [2, 3] |
|---|---|
| ln Vitro |
In chondrocytes, vosoritide (0.1 μM; 1 hour) decreases NPR2 phosphorylation [2]. In cultured Fgfr3Y367C/+ femurs, voyoritide (0.1 μM; 6 days) enhances chondrocyte differentiation and augments proliferative growth plate area [2]. Vosoritide (10 μM; overnight) decreases ACH growth plate chondrocytes' ERK1/2 activation [3].
In human growth plate chondrocytes from individuals with achondroplasia (ACH) harboring the FGFR3 c.1138G>A (p.Gly380Arg) mutation, treatment with BMN-111 (10⁻⁵ M) partially prevented the fibroblast growth factor (FGF)-mediated increase in ERK1/2 phosphorylation. This was assessed by immunoblotting of cell lysates using a phospho-ERK1/2 antibody. In contrast, FGF-mediated STAT3 phosphorylation was not decreased by BMN-111 in these cells. [3] |
| ln Vivo |
Vosoritide (subcutaneous injection; 800 μg/kg; once daily; 20 days) therapy improves skeletal measures in mice with Fgfr3 gain-of-function mutations [3].
In the Fgfr3Y367C/+ mouse model of achondroplasia, subcutaneous administration of BMN-111 led to significant recovery of bone growth. [3] Ex Vivo (Femur Explants): In femurs isolated from E16.5 Fgfr3Y367C/+ mouse embryos, co-incubation with BMN-111 (10⁻⁶ M to 10⁻¹⁰ M) for 6 days resulted in a concentration-dependent increase in femur length. The maximum effect was observed at 10⁻⁶ M. Histological analysis showed a concentration-dependent expansion of the proliferative and hypertrophic zones, with larger and spherical hypertrophic chondrocytes, and an increased hypertrophic zone area as shown by type X collagen staining. [3] In Vivo (10-Day Treatment): Fgfr3Y367C/+ mice treated once daily with subcutaneous BMN-111 (800 μg/kg) for 10 days showed significant growth improvements, including a 5.2% increase in femur length, 5.3% increase in nasoanal length, 6.6% increase in tibia length, 4.8% increase in anterior-posterior skull diameter, and 8.0% increase in tail length compared to vehicle-treated controls (p < 0.05). Histological analysis of the distal femur revealed dose-dependent modifications, including expansion of the prehypertrophic and hypertrophic zones, with larger and more spherical hypertrophic cells. [3] In Vivo (20-Day Treatment): Extended treatment with BMN-111 (800 μg/kg once daily) for 20 days resulted in further phenotypic improvements, including flattening of the skull, elongation of the snout, improvement of the anterior crossbite, longer and straightened tibias and femurs, and longer tails. Histological analysis showed rescue of the growth plate height and architecture, with proliferative and hypertrophic chondrocytes organized in columns. [3] |
| Cell Assay |
Western Blot Analysis[2]
Cell Types: Chondrocyte Culture Tested Concentrations: 0.1 μM Incubation Duration: 1 hour Experimental Results: Result in diminished NPR2 phosphorylation. Western Blot Analysis[3] Cell Types: Chondrocytes Tested Concentrations: 10 μM Incubation Duration: Overnight Experimental Results: Prevents FGF-mediated increase in ERK1/2 phosphorylation. Western Blot Analysis (Human ACH Chondrocytes): Human control and ACH growth plate chondrocytes (harboring the FGFR3 p.Gly380Arg mutation) were isolated and cultured. Cells were pretreated with BMN-111 (10⁻⁵ M) and then co-incubated with FGF18 (100 ng/mL). Cell lysates were subjected to SDS-PAGE and hybridized overnight with a phosphorylated-ERK1/2 antibody. BMN-111 pretreatment partially prevented the FGF-mediated increase in ERK1/2 phosphorylation (n=6). STAT3 phosphorylation was assessed similarly using a phospho-STAT3 antibody, which was not decreased by BMN-111 co-incubation. [3] |
| Animal Protocol |
Animal/Disease Models: Fgfr3Y367C/+ mice[3]
Doses: 800 μg/kg Route of Administration: subcutaneous injection; 800 μg/kg; one time/day; 20 days Experimental Results: Observed phenotypic changes include skull flattening, snout Elongation, front crossbite improvement, claws and fingers enlarged, tibia and femur lengthened and straightened. Ex Vivo Femur Culture: Femurs were dissected from E16.5 Fgfr3Y367C/+ mouse embryos and cultured in DMEM with antibiotics and 0.2% BSA for 6 days. The culture medium was supplemented with BMN-111 at concentrations ranging from 10⁻⁶ M to 10⁻¹⁰ M, or vehicle (control). The left femur was treated, and the right femur served as a control. Bone length was measured at day 0 (D0) and day 6 (D6). [3] In Vivo Mouse Study (10-Day): Fgfr3Y367C/+ and wild-type mice (7 days old) received once-daily subcutaneous administrations of BMN-111 (240 μg/kg or 800 μg/kg) or vehicle (0.03 mol/L acetic acid buffer solution, pH 4.0, containing 1% [w/v] benzyl alcohol and 10% [w/v] sucrose) for 10 days. Dosing occurred approximately 2 hours prior to the dark cycle. Body length, tail length, and various bone segments were measured. [3] In Vivo Mouse Study (20-Day): Fgfr3Y367C/+ and wild-type mice (7 days old) received once-daily subcutaneous administrations of BMN-111 (800 μg/kg) or vehicle for 20 days. Skeletal changes were assessed by X-ray and histological analysis. [3] |
| ADME/Pharmacokinetics |
Absorption
In patients receiving daily subcutaneous injections of vosoritide 15 mcg/kg, the mean Cmax ranged from 4.71-7.18 ng/mL and the mean AUC0-t ranged from 161-290 ng-min/mL. The median Tmax following subcutaneous injection was approximately 15 minutes. Volume of Distribution The mean apparent volume of distribution following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 2880 to 3020 mL/kg. Clearance The mean apparent clearance following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 79.4 to 104 mL/min/kg. Metabolism / Metabolites As with other therapeutic proteins, vosoritide is likely metabolized via catabolic pathways into smaller peptides and amino acids. Biological Half-Life The mean half-life following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 21.0 to 27.9 minutes. BMN-111 is a 39-amino acid CNP analog designed to be resistant to neutral endopeptidase (NEP) digestion, which extends its plasma half-life compared to native CNP. This property allows for once-daily subcutaneous administration. [3] |
| Toxicity/Toxicokinetics |
In Fgfr3Y367C/+ mice treated with BMN-111 (800 μg/kg once daily) for 20 days, the tail was longer and had some kinks, suggesting a potential overdose effect, as similarly seen in mice overexpressing CNP. [3]
Hepatotoxicity In the registration studies submitted in support of approval of vosoritide, “overall, there were no clinically meaningful changes in any laboratory parameter in the clinical program.” Serum ALT levels rose to above the upper limit of normal (ULN) in 22% of vosoritide treated participants vs 18% of controls, but there were no increases above 5 times ULN or elevations accompanied by jaundice or symptoms. Alkaline phosphatase elevations arose in at least 17% of treated patients vs 7% of controls, but the abnormalities were possibly a result of bone growth rather than liver or biliary injury. In the initial clinical trial and in subsequent more widespread use of vosoritide, there have been no reports of clinically apparent liver injury or jaundice. |
| References | |
| Additional Infomation |
See also: Vosoritide (comment moved to).
|
| Molecular Formula |
C176H290N56O51S3
|
|---|---|
| Molecular Weight |
4102.7254
|
| Exact Mass |
4101.101
|
| CAS # |
1480724-61-5
|
| Related CAS # |
Vosoritide acetate
|
| PubChem CID |
119058036
|
| Sequence |
Pro-Gly-Gln-Glu-His-Pro-Asn-Ala-Arg-Lys-Tyr-Lys-Gly-Ala-Asn-Lys-Lys-Gly-Leu-Ser-Lys-Gly-Cys-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys (Disulfide bridge:Cys23-Cys39)
|
| SequenceShortening |
PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Disulfide bridge:Cys23-Cys39)
|
| Appearance |
White to off-white solid at room temperature
|
| LogP |
-20.6
|
| Hydrogen Bond Donor Count |
61
|
| Hydrogen Bond Acceptor Count |
64
|
| Rotatable Bond Count |
112
|
| Heavy Atom Count |
286
|
| Complexity |
9600
|
| Defined Atom Stereocenter Count |
32
|
| SMILES |
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)CC2=CC=CC=C2)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](CC3=CC=C(C=C3)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](CC5=CN=CN5)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 Key |
IGYWDDBBJPSOTG-WBAGYEQSSA-N
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| InChi Code |
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
|
| Chemical Name |
(4R,10S,16S,19S,22S,28S,31S,34S,37S,40S,43S,49S,52R)-52-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-5-amino-5-oxo-2-[[2-[[(2S)-pyrrolidine-2-carbonyl]amino]acetyl]amino]pentanoyl]amino]-4-carboxybutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]hexanoyl]amino]acetyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]hexanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]acetyl]amino]-40-(4-aminobutyl)-49-benzyl-28-[(2S)-butan-2-yl]-31-(3-carbamimidamidopropyl)-34-(carboxymethyl)-16,22-bis(hydroxymethyl)-10,37,43-tris(2-methylpropyl)-19-(2-methylsulfanylethyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51-hexadecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hexadecazacyclotripentacontane-4-carboxylic acid
|
| Synonyms |
Vosoritide; Voxzogo; BMN-111; 1480724-61-5; BMN 111;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O :≥ 50 mg/mL (12.2 mM)
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.2437 mL | 1.2187 mL | 2.4374 mL | |
| 5 mM | 0.0487 mL | 0.2437 mL | 0.4875 mL | |
| 10 mM | 0.0244 mL | 0.1219 mL | 0.2437 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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