Navepegritide
C-type natriuretic peptide on a releasable carrier, injected weekly to speed growth in achondroplasia
Navepegritide is CNP linked to a carrier that releases it steadily, so one weekly injection gives continuous exposure, unlike daily vosoritide. Ascendis's Yuviwel received accelerated approval in the US on February 27, 2026 to increase linear growth in children 2 and older with achondroplasia and open growth plates.
What is it?
Achondroplasia's overactive FGFR3 signalling is opposed by CNP, which vosoritide supplies with a daily injection. Navepegritide's carrier releases CNP over the week, aiming at continuous exposure: the label gives a half-life of 6.7 days for the prodrug and 5.3 days for the CNP it releases.
The slow release was a design choice. In monkeys, the daily CNP molecule lasted about 20 minutes and peaked about a hundredfold higher, while the prodrug kept CNP in circulation for at least a week. Sustained exposure stimulated bone growth more than intermittent exposure, without the drops in blood pressure that followed bolus CNP at equal doses.
In the phase 3 APPROACH trial, 84 children aged 2 to 12 were randomised two to one. After 52 weeks those on navepegritide grew 5.9 cm a year against 4.4 on placebo, a difference of 1.5 cm a year, and their legs straightened slightly. The gain was larger in children aged 5 and over (1.8 cm a year) than in younger ones (1.0). There was no symptomatic hypotension and no fracture. In the earlier dose-finding trial, growth was maintained over two years at the approved dose.
Two trials sit behind the label. The dose-finding trial randomised 57 children three to one to one of four weekly doses, from 0.006 to 0.1 mg/kg, or placebo; the cGMP signal that marks NPR-B activation rose with dose. All 57 then continued on 0.1 mg/kg, and growth held over two years. The molecule itself is large, about 45 kDa, because the 38-amino-acid CNP is attached to two branched 20 kDa polyethylene glycol chains.
As with vosoritide, approval rests on growth velocity, not adult height: it is an accelerated approval, and continued approval may depend on a confirmatory trial. An early trial is pairing it with lonapegsomatropin, weekly growth hormone, and it is being studied in hypochondroplasia.
Yuviwel is injected once a week under the skin, at a dose read from a weight table, from 0.88 mg for children of 8 to 9.9 kg up to 8.8 mg at 73.6 to 90 kg. Children already on daily CNP switch the day after their last daily dose. Treatment stops when the growth plates close. Vomiting, injection-site reactions, limb pain and nausea were the reactions more common than on placebo.
Mechanism of Action
Navepegritide is a prodrug: CNP-38 joined by the TransCon linker to a polyethylene glycol carrier, releasing CNP that acts like the body's own on the NPR-B receptor in growth plates (label).
NPR-B receptor
Released CNP binds NPR-B, raising cGMP and signalling through protein kinase G (label).
Counters FGFR3
This inhibits the MAPK pathway that overactive FGFR3 drives in achondroplasia, so growth-plate chondrocytes proliferate and differentiate (label).
A week of CNP
The linker cleaves on its own; steady state comes after about three weekly doses, and released CNP has a half-life of about 5.3 days (label).
Published Research
Trials read from their PubMed abstracts, with the approval review; dosing from the Yuviwel label read October 1, 2026.
APPROACH
In 84 children with achondroplasia randomised 2:1, weekly navepegritide raised annualised growth velocity at 52 weeks by 1.49 cm a year over placebo and improved leg alignment (tibial-femoral angle -1.81°), with low injection-site reaction rates, no symptomatic hypotension or fractures, and two discontinuations.
ACcomplisH (phase 2)
Children on navepegritide gained height SDS against placebo (0.22 against -0.08, p = 0.028); all completed the randomised period and continued on 100 µg CNP/kg weekly.
Phase 1 in healthy adults
Single doses gave a pharmacokinetic profile compatible with weekly dosing and raised CNP-related signalling for at least a week, with no serious events and no clinically relevant ECG effects.
Combined with lonapegsomatropin
In a prospective trial pairing it with weekly growth hormone, children grew robustly, body proportions improved and arm span rose 9.4 and 7.9 cm in the two groups, with mild adverse events and no discontinuations.
First approval
A drug review recording US accelerated approval for increasing linear growth in children 2 and older with achondroplasia, and noting its investigation in hypochondroplasia.
Why release it slowly
In mice and monkeys, sustained CNP from the prodrug stimulated bone growth more than intermittent CNP, without the blood-pressure falls and heart-rate rises seen at equal doses of short-acting CNP; released CNP had a half-life of about 90 hours in monkeys against 20 minutes for a daily CNP molecule.
Dosing Data
Yuviwel is a once-weekly injection under the skin, dosed from the label's weight table and adjusted as the child grows, until the growth plates close.
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Side Effects & Contraindications
Reported Side Effects
From the placebo-controlled periods of the two trials, as pooled in the Yuviwel label.
Contraindications & Cautions
From the label.
Legal Status
Approved in the US under accelerated approval, based on growth velocity; continued approval may depend on a confirmatory trial showing clinical benefit.
Frequently Asked Questions
?How is it different from vosoritide?
Both supply CNP activity; vosoritide is injected daily and clears in under half an hour, navepegritide once a week with a 6.7-day half-life.
?Does it increase adult height?
Not shown yet: accelerated approval rests on growth velocity.
?Can it be combined with growth hormone?
A 2026 trial paired it with lonapegsomatropin and reported robust growth; that use is not on the label.
?How much faster do children grow?
In the APPROACH trial, children on navepegritide grew 5.9 cm a year against 4.4 cm on placebo over 52 weeks, a difference of 1.5 cm a year. The difference was 1.8 cm a year in children aged 5 and older and 1.0 in those under 5.
?How is the dose chosen?
By body weight, from a table on the label: for example 1.6 mg a week for a child of 13.5 to 17.5 kg and 2.8 mg for 23.1 to 30.5 kg. The dose is adjusted as the child gains weight.
?What are the side effects?
In the placebo-controlled trials, vomiting (21% against 14%), injection-site reactions (19% against 14%), limb pain and nausea were more common on navepegritide. Two children of 68 had extra hair growth, so injection sites are rotated.
?What if a dose is missed?
The label allows each weekly dose to be given up to 2 days before or after the scheduled day, at any time of day, which gives families some room before a dose counts as missed.
?Does it affect the heart or blood pressure?
At the approved dose it did not prolong the QT interval to any clinically relevant extent. The label warns that transient falls in blood pressure have been reported with a daily CNP analogue, and children with significant heart disease were excluded from the trials; in APPROACH there was no symptomatic hypotension.
?How is it prepared and stored?
It comes as a powder that families mix at home with the sterile water in a prefilled syringe, after training: the vial is shaken for 15 seconds, not swirled, and used within 4 hours. Unopened, it is kept in the fridge, or at room temperature up to 30°C for up to 6 months. Heavier children use two kits per dose.
?When does treatment stop?
When the growth plates close and there is no more growth potential, the label says to stop. Until then the dose is reviewed as the child gains weight.
?What is known about long-term safety?
Clinical follow-up runs to about two years at the approved dose, with growth maintained. In the label's animal and laboratory work it was not genotoxic and did not affect fertility in rats at three to four times the human exposure, but long-term cancer studies in animals have not been done, and safety under age 2 is not established.
References
- [fda-pi] Yuviwel (navepegritide) for injection US prescribing information (DailyMed version 4, effective March 25, 2026); read October 1, 2026.
- [clinical-trial] Savarirayan R, et al. "Once-Weekly Navepegritide in Children With Achondroplasia: The APPROACH Randomized Clinical Trial." JAMA Pediatr, 2026;180(1):18-25. PMID: 41247754.
- [clinical-trial] Savarirayan R, et al. "Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial." EClinicalMedicine, 2023;65:102258. PMID: 37823031.
- [clinical-trial] Breinholt VM, et al. "Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long-acting C-type natriuretic peptide prodrug, TransCon CNP." Br J Clin Pharmacol, 2022;88(11):4763-4772. PMID: 35481707.
- [clinical-trial] McDonnell CM, et al. "Navepegritide combined with lonapegsomatropin for the treatment of children with achondroplasia: 52-week results from the phase 2 COACH trial." Eur J Endocrinol, 2026;194(6):745-755. PMID: 42144862.
- [review] Kang C. "Navepegritide: First Approval." Drugs, 2026;86(8):1385-1391. PMID: 42234372.
- [pubmed] Breinholt VM, et al. "TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3-Related Skeletal Dysplasias." J Pharmacol Exp Ther, 2019;370(3):459-471. PMID: 31235532.
Sources & Citations
Studies were read from their PubMed abstracts; the Yuviwel label (DailyMed version 4, effective March 25, 2026) was read October 1 and October 6, 2026.
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