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Navepegritide, to be marketed as YUVIWEL, is the only FDA-approved treatment providing continuous CNP exposure over its weekly dosing interval.
The United States (US) Food and Drug Administration (FDA) has granted accelerated approval to navepegritide (YUVIWEL), a once-weekly C-type natriuretic peptide (CNP) analog, to increase linear growth in children aged 2 years and older with achondroplasia and open epiphyses. The decision was based on improvements in annualized growth velocity (AGV) from 3 phase 3 trials, with continued approval contingent on confirmatory evidence of clinical benefit.1
“The approval of once-weekly YUVIWEL is a major step forward in the treatment of children with achondroplasia, giving physicians for the first time the option of prescribing a once-weekly medicine backed by compelling efficacy and excellent tolerability data from three randomized, double-blind, placebo-controlled clinical trials,” Carlos A. Bacino, MD, FACMG, Professor of Molecular and Human Genetics, Baylor College of Medicine and Texas Children’s Hospital, said in Ascendis Pharma’s statement.1 “My goal is to help children and parents develop care plans tailored to their individual needs and objectives, and I look forward to adding YUVIWEL to my discussions with them.”
Achondroplasia, the most common form of disproportionate short stature, is caused by activating variants in fibroblast growth factor receptor 3 (FGFR3), resulting in impaired endochondral ossification. Beyond short stature, affected individuals face increased risks of foramen magnum stenosis, spinal stenosis, sleep-disordered breathing, and other neurologic and orthopedic complications.1 Therapeutic strategies have focused on modulating the overactive FGFR3 pathway, including use of CNP analogs to counterbalance signaling at the growth plate.
“Little People of America, the largest national advocacy and support organization for people with dwarfism, is committed to ensuring that the voices of people with dwarfism remain central in conversations about research and medical options such as YUVIWEL,” said the Board of Directors of Little People of America.1 “We champion dwarf and disability pride, advocate for inclusion and respect, and foster open dialogue across diverse perspectives. Our goal is to empower individuals and families to make healthcare decisions that reflect their own values and experiences, while pushing for research efforts and new treatment options such as this that could have the potential to support outcomes that truly matter to our community.”
The FDA’s decision was supported by 3 randomized, double-blind, placebo-controlled trials of navepegritide, including the pivotal phase 3 ApproaCH study, as well as open-label extension data of up to 3 years. Detailed results from the phase 3 trial have been published in JAMA Pediatrics.2 In that study, once-weekly navepegritide significantly increased AGV compared with placebo in children with achondroplasia. The most commonly reported adverse events (AEs) were injection-site reactions and mild, transient hypotension; serious AEs were infrequent.
Navepegritide was approved under the accelerated approval pathway based on increased AGV as a surrogate outcome reasonably likely to predict clinical benefit. Confirmatory trials will be required to verify longer-term functional outcomes, such as adult height, complication rates, or quality-of-life measures.1
“We are confident in YUVIWEL’s potential to transform the treatment of achondroplasia and are deeply grateful to patients, clinicians, and advocates for their many contributions to this important milestone,” Jan Mikkelsen, President and Chief Executive Officer at Ascendis Pharma, added.1 “We have listened to advocacy groups for people with dwarfism to ensure we address what the community actually cares about. This reflects our ongoing commitment to pursue outcomes that patient communities have told us are important to them, and gives the achondroplasia community a new way to look at the promise of pharmacological treatment options.”
Drug: Navepegritide (YUVIWEL)
Class: C-type natriuretic peptide analog (prodrug)
Indication: Increase linear growth in children ≥2 years with achondroplasia and open epiphyses
Regulatory Action: FDA accelerated approval (February 2026)
Pivotal Trial: Phase 3 ApproaCH
Key Efficacy Outcome: Increased annualized growth velocity vs placebo
Key Safety Signals: Injection-site reactions; transient hypotension
CNP is an endogenous peptide that promotes endochondral bone growth by antagonizing the MAPK pathway downstream of FGFR3. By enhancing CNP signaling, navepegritide aims to offset the constitutive FGFR3 activation characteristic of achondroplasia. As with other CNP analogs, blood pressure monitoring is recommended given the peptide’s vasodilatory properties.1
Until 2021, management of achondroplasia was largely supportive and surgical. In November 2021, the FDA approved vosoritide, a daily CNP analog, to increase growth velocity in children with open growth plates.3 Vosoritide demonstrated an approximate 1.6 cm/year increase in AGV compared with placebo in a phase 3 trial.4
Navepegritide represents an alternative CNP-based approach, designed as a prodrug to provide sustained systemic CNP exposure over a weekly dosing interval. Whether once-weekly dosing translates into differences in adherence, tolerability, or long-term outcomes compared with daily therapy remains to be established in comparative studies.
As with vosoritide, the clinical relevance of increased childhood growth velocity to long-term morbidity—such as need for orthopedic procedures, neurologic complications, or adult functional status—remains under investigation.
