| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
Prodrug of C-type natriuretic peptide (CNP); METABOLITE ACTIVE
The C-type natriuretic peptide released from navepegritide targets and activates the natriuretic peptide receptor-B (guanylyl cyclase B; NPR-B). In achondroplasia, a gain-of-function variant in fibroblast growth factor receptor 3 leads to overactive downstream signaling that inhibits endochondral ossification. CNP binding to NPR-B stimulates cGMP production and signaling through protein kinase G, resulting in inhibition of the MAPK signaling pathway, thereby antagonizing overactive FGFR3 signaling in achondroplasia. The agonist activity at NPR-B is expected to be similar to that of endogenous CNP-38. |
|---|---|
| ln Vitro |
Navepegritide is inactive when bound to the PEG carrier and releases active C-type natriuretic peptide via linker cleavage upon exposure to physiologic pH and temperature. The released C-type natriuretic peptide has the same receptor binding affinity and activity as endogenous CNP. In human chondrocytes, CNP binds to NPR-B, stimulating cGMP production and inhibiting the MAPK pathway via PKG signaling, thereby counteracting the FGFR3-mediated inhibition of chondrocyte hypertrophy and differentiation.
|
| ln Vivo |
The phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 μg CNP/kg/week in the ongoing pivotal trial.[1,2,3]
In the phase 2b randomized, double-blind, placebo-controlled APPROACH trial (NCT05598320), 84 children aged 2-11 years with achondroplasia were randomized to receive navepegritide (100 μg/kg/week, n=57) or placebo (n=27) for 52 weeks. The primary endpoint was met: annualized growth velocity at week 52 was 5.89 cm/year in the navepegritide group vs. 4.41 cm/year in the placebo group, with a least-squares mean treatment difference of 1.49 cm/year (95% CI: 1.05-1.93; P<0.001). Secondary endpoints showed improvements in navepegritide-treated patients in tibial-femoral angle (LS mean difference -1.81°), mechanical axis deviation (-2.78 mm), and fibula-to-tibia length ratio (-0.016). In children younger than 5 years, Achondroplasia Child Experience Measures-Physical Functioning improved by -11.1 (95% CI: -21.5 to -0.80). In children aged 5 years and older, navepegritide treatment improved annualized growth velocity by approximately 5.4 cm/year compared to baseline. |
| Enzyme Assay |
Based on its prodrug design, the active CNP-38 moiety has identical receptor binding properties to endogenous C-type natriuretic peptide.
|
| Animal Protocol |
Methods: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 μg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22).[3]
Findings: Forty-two participants received TransCon CNP at doses of 6 μg (n = 10; 7 female), 20 μg (n = 11; 3 female), 50 μg (n = 10; 3 female), or 100 μg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 μg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 μg CNP/kg/week.[3] Interpretation: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 μg CNP/kg/week in the ongoing pivotal trial.[3] |
| ADME/Pharmacokinetics |
Prolonged Half-Life: Navepegritide achieves a significantly prolonged half-life through TransCon technology, supporting once-weekly dosing. Active CNP is released from the carrier in a controlled, sustained manner following first-order kinetics.
Peak Concentration Control: The prodrug design achieves a low Cmax by providing continuous, sustained exposure to active CNP.
Dosing Regimen: Once-weekly subcutaneous injection at a dose of 100 μg/kg body weight.
Pharmacokinetic Modeling: A semi-mechanistic model has been developed to describe the pharmacokinetics of navepegritide and the prolonged half-life of CNP.
|
| Toxicity/Toxicokinetics |
During the 52-week treatment period of the APPROACH trial, navepegritide was generally well tolerated with a safety profile similar to placebo. Approximately 99% of treatment-emergent adverse events were mild (Grade 1) or moderate (Grade 2); no adverse events led to trial withdrawal or treatment discontinuation. The incidence of injection site reactions was low in both groups (19.3% in the navepegritide group vs. 14.8% in the placebo group), with all being mild. Asymptomatic hypotension was documented in two participants in each group (3.5% in the navepegritide group vs. 7.4% in the placebo group), none considered treatment-related. No symptomatic hypotension or fractures were observed. The most common adverse reactions (≥5% and greater than placebo) include vomiting, injection-site reactions, pain in extremity, and nausea; hypertrichosis was less common (3%). Yuviwel has a warning for low blood pressure risk, as transient decreases in blood pressure have been reported with a once-daily CNP analog.
|
| References |
[1]. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00435-2/fulltext.
[2]. https://drugs.ncats.io/substance/Y3BH8M899D. [3]. Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial. EClinicalMedicine . 2023 Oct 2:65:10225 |
| Molecular Formula |
C175H291N55O50S3
|
|---|---|
| Molecular Weight |
4061.72
|
| CAS # |
2413551-27-4
|
| Sequence |
C-Type natriuretic peptide (CNP), human, (89-126)-fragment (1-38) (CNP-38), conjugated at N6 of Lys26 with four O-methylpoly(ethylene glycol) chains (approx. 10 kDa each) via a cleavable tetra-antennary linker; L-leucyl-L-glutaminyl-L-α-glutamyl-L-histidyl-L-prolyl-L-asparaginyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysylglycyl-L-alanyl-L-asparaginyl-L-lysyl-L-lysylglycyl-L-leucyl-L-seryl-L-lysylglycyl-L-cysteinyl-L-phenylalanylglycyl-L-leucyl-N6-{N2-[N2,N6-bis(6-{[(3RS)-1-{3-[(3-{(2RS)-2,3-bis[α-methylpoly(oxyethylene)-ω-oxy]propoxy}propyl)amino]-3-oxopropyl}-2,5-dioxopyrrolidin-3-yl]sulfanyl}hexanoyl)-L-lysyl]-N2-methyl-N1-[2-(methylamino)ethyl]-L-isoasparaginyl}-L-lysyl-L-leucyl-L-α-aspartyl-L-arginyl-L-isoleucylglycyl-L-seryl-L-methionyl-L-serylglycyl-L-leucylglycyl-L-cysteine (22-38)-disulfide
Poly(oxy-1,2-ethanediyl), α-hydro-ω-methoxy-, 26,26,26,26-tetraether with L-leucyl-L-glutaminyl-L-α-glutamyl-L-histidyl-L-prolyl-L-asparaginyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysylglycyl-L-alanyl-L-asparaginyl-L-lysyl-L-lysylglycyl-L-leucyl-L-seryl-L-lysylglycyl-L-cysteinyl-L-phenylalanylglycyl-L-leucyl-N6-[N2,N6-bis[6-[[1-[3-[[3-(2,3-dihydroxypropoxy)propyl]amino]-3-oxopropyl]-2,5-dioxo-3-pyrrolidinyl]thio]-1-oxohexyl]-L-lysyl-N2-methyl-N-[2-(methylamino)ethyl]-L-α-asparaginyl]-L-lysyl-L-leucyl-L-α-aspartyl-L-arginyl-L-isoleucylglycyl-L-seryl-L-methionyl-L-serylglycyl-L-leucylglycyl-L-cysteine cyclic (22→38)-disulfide |
| SequenceShortening |
POLY(OXY-1,2-ETHANEDIYL), .ALPHA.-HYDRO-.OMEGA.-METHOXY-, 26,26,26,26-TETRAETHER WITH L-LEUCYL-L-GLUTAMINYL-L-.ALPHA.-GLUTAMYL-L-HISTIDYL-L-PROLYL-L-ASPARAGINYL-L-ALANYL-L-ARGINYL-L-LYSYL-L-TYROSYL-L-LYSYLGLYCYL-L-ALANYL-L-ASPARAGINYL-L-LYSYL-L-LYSYLGLYC
|
| Appearance |
Typically exists as solid at room temperature
|
| Synonyms |
CNP-38; CNP38
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO: 50 mg/mL (12.3 mM)
Note: Please refer to page 4 in the "Instructions for use" file (upper-right section of this webpage) for how to dissolve peptides. |
|---|---|
| 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 | 0.2462 mL | 1.2310 mL | 2.4620 mL | |
| 5 mM | 0.0492 mL | 0.2462 mL | 0.4924 mL | |
| 10 mM | 0.0246 mL | 0.1231 mL | 0.2462 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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