Navepegritide

Ascendis Pharma's TransCon CNP, a once-weekly PEGylated prodrug of a 38-residue C-type natriuretic peptide, approved by the FDA on February 27, 2026 as Yuviwel to increase linear growth in children aged 2 and older with achondroplasia.

Also referenced as: TransCon CNP, Yuviwel

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What is Navepegritide?

Navepegritide, developed by Ascendis Pharma as TransCon CNP, is a long-acting prodrug of C-type natriuretic peptide (CNP) for achondroplasia. It is not a bare peptide but a PEGylated conjugate: a 38-amino-acid peptide identical to residues 89 through 126 of human CNP, usually written CNP-38, is transiently attached through a proprietary TransCon linker to two branched 20 kDa methoxy-polyethylene glycol carriers. The US label gives the molecular formula as C231H386N64O67S5 plus four polyethylene glycol chains of 200 to 250 repeat units each, for an average molecular weight of about 45 kDa. Because CNP-38 ends at residue 126, it carries the 22-residue, disulfide-ringed mature CNP-22 at its C-terminus with a 16-residue N-terminal extension. After subcutaneous injection the linker cleaves by itself with first-order kinetics, releasing unmodified CNP-38 continuously across a weekly interval, and the peptide is then cleared through ordinary peptide degradation.

Achondroplasia is caused by a gain-of-function variant in fibroblast growth factor receptor 3 (FGFR3) that suppresses endochondral bone growth, and CNP signaling is the natural counterweight to FGFR3 in the growth plate. Navepegritide was approved by the FDA on February 27, 2026 as Yuviwel to increase linear growth in children aged 2 years and older with achondroplasia and open epiphyses, the second CNP-based therapy for the condition after the daily analog vosoritide and the first given weekly. It shares the TransCon prodrug platform with palopegteriparatide and lonapegsomatropin and has no presence in the research-peptide market.

How it works

• NPR-B agonism that antagonizes overactive FGFR3. CNP released from navepegritide has the same receptor affinity and activity as endogenous CNP. It binds natriuretic peptide receptor-B (NPR-B) on growth-plate chondrocytes, raising cyclic GMP and signaling through protein kinase G, which inhibits the MAP kinase cascade downstream of mutant FGFR3 and restores chondrocyte proliferation and differentiation; the label describes the mechanism in these terms, and the preclinical paper that introduced the conjugate framed it as treatment of FGFR3-related skeletal dysplasias (Breinholt et al., Journal of Pharmacology and Experimental Therapeutics, 2019;370(3):459–471).
• Continuous rather than pulsed CNP exposure. In mice and cynomolgus monkeys, sustained CNP delivered as TransCon CNP stimulated bone growth more effectively than intermittent CNP. In monkeys the released CNP-38 had an estimated half-life of 90 hours against 20 minutes for a daily CNP-39 molecule with the vosoritide sequence, peak CNP levels were roughly 100-fold lower than after CNP-39, and the blood-pressure falls and heart-rate rises seen with unconjugated CNP did not occur with the prodrug at exposures above the expected therapeutic range (Breinholt et al., Journal of Pharmacology and Experimental Therapeutics, 2019;370(3):459–471).
• Target engagement for at least a week in humans. In a randomized, placebo-controlled single-ascending-dose study of 45 healthy adult men at two Australian sites, TransCon CNP at 3 to 150 µg CNP/kg gave continuous CNP exposure for at least 7 days, plasma and urine cyclic GMP rose significantly at 75 to 150 µg CNP/kg, and cardiac monitoring found no clinically relevant effect on heart rate, PR, QRS or QTcF intervals (Breinholt et al., British Journal of Clinical Pharmacology, 2022;88(11):4763–4772); in treated children the label gives a half-life of 6.7 days for navepegritide and 5.3 days for released CNP, with steady state after about three weekly doses.

Research status

ACcomplisH (NCT04085523). A global, double-blind, placebo-controlled, dose-escalation phase 2 trial randomized 57 prepubertal children aged 2 to 10 with genetically confirmed achondroplasia 3:1 to weekly TransCon CNP at 6, 20, 50 or 100 µg CNP/kg or placebo for 52 weeks; 42 received active drug and 15 placebo. Annualized growth velocity improved dose-dependently, and at 100 µg CNP/kg/week the least-squares mean was 5.42 cm/year versus 4.35 cm/year with placebo (p = 0.0218), with achondroplasia-specific height SDS changing by +0.22 versus −0.08 (p = 0.0283). All treatment-emergent adverse events were mild or moderate, the two serious events were judged unrelated, 11 injection-site reactions occurred in 8 treated participants, and no symptomatic hypotension was seen; every participant entered the open-label extension at the top dose (Savarirayan et al., EClinicalMedicine, 2023;65:102258). The label states that growth velocity was maintained in participants who completed two years at that dose. A parallel 24-child study in China, ACcomplisH China (NCT05246033), completed on April 23, 2024 and has no results posted on the registry.

ApproaCH (NCT05598320). The pivotal trial, described by its authors as phase 2b and listed on the registry as phase 2/3, enrolled 84 treatment-naive children aged 2 to 11 at 10 hospitals in seven countries between March and August 2023 and randomized them 2:1 to navepegritide 100 µg/kg weekly (n = 57) or placebo (n = 27) for 52 weeks, followed by an open-label extension. The primary endpoint was met: annualized growth velocity at week 52 was higher by a least-squares mean of 1.49 cm/year (95% CI 1.05 to 1.93; p < 0.001), which the label reports as 5.9 versus 4.4 cm/year, with a 0.3 gain in achondroplasia-specific height Z-score. Tibial-femoral angle changed by −1.81°, mechanical axis deviation by −2.78 mm and the fibula-to-tibia length ratio by −0.016, and the Achondroplasia Child Experience Measures physical-functioning score moved by −11.1 points in children under 5, reported as an improvement. No serious adverse event was treatment-related, there were no deaths, fractures or symptomatic hypotension, and two treated children discontinued (Savarirayan et al., JAMA Pediatrics, 2026;180(1):18–25). The label notes a smaller treatment difference in children under 5 (1.0 cm/year) than in those 5 and older (1.8 cm/year). The trial reached primary completion on August 9, 2024 and completed on August 13, 2025.

COACH combination trial (NCT06433557). An open-label, single-arm phase 2 study gave weekly navepegritide together with the growth hormone prodrug lonapegsomatropin to 21 children aged 2 to 11, 12 treatment-naive and 9 already on navepegritide for more than a year. At week 52, treatment-naive children had a least-squares mean annualized growth velocity of 8.69 cm/year against 5.95 cm/year in matched monotherapy participants from ApproaCH, a difference of 2.74 cm/year (p < 0.0001); navepegritide-experienced children grew 8.42 cm/year. Adverse events were generally mild with no discontinuations (McDonnell et al., European Journal of Endocrinology, 2026;194(6):745–755). The 156-week study runs to November 2027.

Pooled evidence on CNP analogs. A meta-analysis of vosoritide and navepegritide pooled 4 low-risk-of-bias randomized trials (326 children): CNP analogs raised annualized growth velocity by a mean 1.36 cm/year (95% CI 1.05 to 1.68) and standing height by 1.24 cm, had no short-term effect on upper-to-lower body segment ratio, and matched placebo for serious adverse events apart from higher relative risks of injection-site reactions (1.65), urticaria (4.04) and swelling (3.57); the authors called the gains slight but statistically meaningful (Kamrul-Hasan et al., Journal of the Endocrine Society, 2026;10(7):bvag121).

Regulatory path. The new drug application carried an original target action date of November 30, 2025. On November 5, 2025 Ascendis submitted additional information about a post-marketing requirement, which the FDA treated as a major amendment, extending the review by three months to February 28, 2026. NDA 219164 was approved on February 27, 2026 under the accelerated approval pathway on the basis of improved annualized growth velocity, with continued approval contingent on verification of clinical benefit in confirmatory trials; it was the molecule’s first approval anywhere (Kang, Drugs, 2026;86(8):1385–1391). In the European Union, the Committee for Medicinal Products for Human Use adopted a positive opinion on October 15, 2026 recommending marketing authorization for children aged 2 and older whose epiphyses are not closed, and the European Commission’s decision was pending as of November 2026.

Ongoing and planned trials. A long-term open-label extension (NCT05929807) that began on June 21, 2023 is enrolling by invitation up to 140 children and adolescents from the earlier trials and runs to March 2039. A placebo-controlled phase 2 trial in 72 infants under 2 years (NCT06079398) is recruiting toward primary completion in December 2027, and a phase 2b trial in 25 adolescents aged 12 to 18 (NCT06732895) has finished enrolling with an estimated primary completion of September 2027. A phase 3 placebo-controlled trial in 81 children and adolescents with hypochondroplasia (NCT07917143) was listed as not yet recruiting as of November 2026, with primary completion planned for October 2028.

Common dosage forms

• Yuviwel for injection. Single-dose vials of lyophilized powder in 1.3 mg, 2.8 mg and 5.5 mg strengths, expressed as CNP(89-126), supplied with diluent as kits of four per carton, for subcutaneous use by a patient or caregiver trained by a healthcare provider.
• No other presentation. No pen, prefilled drug syringe, oral or compounded form exists.

Key considerations

• Regulatory status. The FDA Approved status reflects the February 27, 2026 accelerated approval of Yuviwel (navepegritide) for injection under NDA 219164 to increase linear growth in pediatric patients aged 2 years and older with achondroplasia with open epiphyses. Continued approval may depend on confirmation of clinical benefit in confirmatory trials, and a positive CHMP opinion adopted on October 15, 2026 awaited a European Commission decision as of November 2026.
• The approval rests on a growth-velocity surrogate. The pivotal result is a 1.5 cm/year advantage over placebo across one year, smaller in children under 5. Whether weekly navepegritide changes adult height, body proportion, spinal or foramen magnum complications or long-term function is unknown; the open-label extension runs to 2039.
• Tolerability so far is mild. The label carries no contraindications and a single warning, about low blood pressure, inherited from the CNP-analog class; vomiting, injection-site reactions and extremity pain were the only adverse events that clearly exceeded placebo in the pooled controlled periods.
• A conjugate, not a peptide, and not interchangeable with vosoritide. Navepegritide is a 45 kDa PEGylated prodrug whose strengths are expressed as the CNP(89-126) it releases; vosoritide is a 39-residue CNP analog given daily, and the two have not been compared head to head. TransCon CNP, navepegritide and Yuviwel denote the same product, while palopegteriparatide and lonapegsomatropin are different TransCon products.
• Combination and new indications remain exploratory. The COACH figures with lonapegsomatropin come from 21 children compared against external controls, and the hypochondroplasia phase 3 trial had not begun enrolling as of November 2026, so neither use is supported by the approved label.