Lonapegsomatropin
High EvidenceLonapegsomatropin (brand name Skytrofa, developed as TransCon hGH by Ascendis Pharma) is a long-acting, once-weekly prodrug of human growth hormone (somatropin) approved to treat growth hormone deficiency (GHD). Unlike conventional recombinant growth hormone, which must be injected every day, lonapegsomatropin uses Ascendis's TransCon ("transient conjugation") technology to slowly release fully active, unmodified growth hormone from an inert carrier over the course of a week, so patients inject only once weekly. It is built from three parts - unmodified somatropin, a methoxypolyethylene glycol (mPEG) carrier that shields the hormone and extends its time in the body, and a TransCon linker that connects them and then self-cleaves at normal body pH and temperature to release native growth hormone at a controlled, predictable rate. The FDA first approved lonapegsomatropin in August 2021 for children one year and older with GHD (the pivotal Phase 3 heiGHt trial showed it was non-inferior and numerically superior to daily somatropin for annualized height velocity in treatment-naive children), and in July 2025 the FDA expanded approval to adults with GHD based on the Phase 3 foresiGHt trial, in which once-weekly TransCon hGH significantly reduced trunk fat and increased lean body mass versus placebo. It is administered subcutaneously with the SKYTROFA Auto-Injector using a single-dose, dual-chamber prefilled cartridge. Lonapegsomatropin is a regulated prescription medicine, not a supplement or research chemical, and shares the class safety profile of growth hormone therapy.
What It Is
Lonapegsomatropin (Skytrofa; developed as TransCon hGH) is a once-weekly, long-acting form of human growth hormone from Ascendis Pharma, designed to solve one of the main problems with traditional growth hormone therapy: the burden and inconsistent adherence of daily subcutaneous injections. Recombinant human growth hormone (somatropin) has been used for decades to treat growth hormone deficiency (GHD) in children and adults, but its short half-life requires injections six or seven days a week for years. Lonapegsomatropin is a prodrug that releases the very same molecule - unmodified somatropin - but only once a week. It is made of three components: the native growth hormone itself, an inert methoxypolyethylene glycol (mPEG) carrier, and a proprietary TransCon linker that transiently binds the hormone to the carrier. While bound, the growth hormone is shielded from receptor binding and renal clearance, which greatly extends its circulation time; at physiologic pH and temperature the linker undergoes controlled autocleavage that follows predictable first-order kinetics, steadily liberating fully active, unmodified growth hormone throughout the week. Because the released molecule is identical to endogenous growth hormone, it distributes and signals like natural somatropin rather than as a chemically altered analog. The FDA approved lonapegsomatropin for pediatric GHD in August 2021 - the first once-weekly growth hormone product cleared in the United States for children - on the strength of the Phase 3 heiGHt trial (NCT02781727), in which treatment-naive children with GHD achieved annualized height velocity that was non-inferior and numerically higher than daily somatropin, with a comparable safety profile. Long-term extension data from the enliGHten trial (NCT03344458) showed sustained catch-up growth, with mean height standard deviation score approaching the average-stature range over multiple years of treatment. A separate switch trial (fliGHt) supported transitioning children already on daily growth hormone, and the InsiGHTS trial met its primary objective in Turner syndrome. In July 2025 the FDA expanded the label to adults with GHD based on the Phase 3 foresiGHt trial (259 adults randomized to weekly TransCon hGH, weekly placebo, or daily somatropin), where weekly lonapegsomatropin significantly reduced trunk fat and increased total lean body mass versus placebo at week 38. Lonapegsomatropin is delivered subcutaneously via the SKYTROFA Auto-Injector using a dual-chamber prefilled cartridge (hormone in one chamber, diluent in the other). It is a prescription biologic with the established warnings and contraindications of growth hormone therapy, and it is not a supplement, nootropic, or research chemical.
Regulatory Status
FDA-approved. Lonapegsomatropin-tcgd (Skytrofa) was approved by the U.S. FDA in August 2021 for the treatment of pediatric patients one year and older who weigh at least 11.5 kg and have growth failure due to inadequate secretion of endogenous growth hormone (growth hormone deficiency). In July 2025 the FDA expanded approval to include adults with growth hormone deficiency, based on the Phase 3 foresiGHt trial. Lonapegsomatropin is also approved in the European Union and additional markets for children with GHD. It is a once-weekly subcutaneous prodrug of somatropin administered with the SKYTROFA Auto-Injector; pediatric dosing is individualized (approximately 0.24 mg/kg once weekly) and adult dosing is individualized and titrated (for example, a starting dose around 2.1 mg/week in adults not using oral estrogen). It carries the standard growth hormone class warnings and contraindications, including acute critical illness, active malignancy, and certain other conditions.
Effective: 2025-07-28
View FDA SourceWhy Researchers Study It
Lonapegsomatropin matters because it is one of the first successful attempts to convert a decades-old daily therapy into a genuinely once-weekly one without changing the active molecule - a proof of concept for prodrug depot chemistry that many other fields are watching. Growth hormone deficiency requires years of treatment, and daily injections are a well-documented cause of missed doses and poorer growth outcomes, so a long-acting formulation that delivers the identical native hormone addresses a real adherence problem rather than merely offering convenience. Researchers and clinicians study lonapegsomatropin to understand how Ascendis's TransCon technology releases unmodified somatropin at a controlled first-order rate, whether weekly exposure reproduces the efficacy and safety of daily dosing (it did on annualized height velocity in the heiGHt trial and on body composition in the adult foresiGHt trial), and how it compares with the other long-acting growth hormones somapacitan and somatrogon. The same TransCon platform now underlies approved and investigational hormone therapies for other conditions - palopegteriparatide (TransCon PTH) for hypoparathyroidism and navepegritide (TransCon CNP) for achondroplasia - so lonapegsomatropin also serves as the flagship example of how a sustained-release prodrug approach can be applied across endocrinology.
Proposed Mechanisms
- Prodrug release of unmodified growth hormone: lonapegsomatropin is somatropin transiently bound to an inert carrier; at physiologic pH and temperature the TransCon linker self-cleaves (autohydrolysis) to release fully active, native human growth hormone in a controlled manner.
- First-order sustained release for weekly dosing: the autocleavage follows predictable first-order kinetics, producing a steady weekly release profile from a single subcutaneous injection instead of daily peaks and troughs.
- Carrier shielding to extend half-life: the methoxypolyethylene glycol (mPEG) carrier shields the bound hormone from growth hormone receptor binding and renal excretion, greatly prolonging its circulation time until the linker releases it.
- Native GH receptor signaling and IGF-1 induction: once released, the unmodified hormone binds the growth hormone receptor and stimulates hepatic and peripheral production of insulin-like growth factor 1 (IGF-1), which mediates linear bone growth in children and anabolic and metabolic effects in adults.
- Body-composition effects in adults: by restoring physiologic growth hormone signaling, lonapegsomatropin reduces visceral and trunk fat and increases lean body mass, the endpoints on which its adult growth hormone deficiency approval was based.
Evidence Snapshot
| Study Type | Model | Outcome | Link |
|---|---|---|---|
| Phase 3 randomized, open-label, active-controlled trial (heiGHt; NCT02781727) in treatment-naive children with growth hormone deficiency | 161 prepubertal, treatment-naive children with GHD randomized 2:1 to once-weekly lonapegsomatropin (TransCon hGH) versus daily somatropin for 52 weeks; primary endpoint annualized height velocity at week 52. | Once-weekly lonapegsomatropin met non-inferiority and was numerically superior on annualized height velocity (about 11.2 cm/year vs about 10.3 cm/year for daily somatropin) with a comparable safety and tolerability profile, supporting the first U.S. pediatric approval of a once-weekly growth hormone (2021). | Source |
| Phase 3 randomized, double-blind, placebo- and active-controlled trial (foresiGHt) in adults with growth hormone deficiency | 259 adults with GHD (ages 23-80) randomized 1:1:1 to once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin; key endpoints trunk fat and lean body mass at week 38. | Weekly lonapegsomatropin achieved superiority over placebo, with a statistically significant reduction in trunk percent fat and an increase in total lean body mass, supporting the July 2025 FDA approval for adult GHD. | Source |
| Phase 3 long-term open-label extension (enliGHten; NCT03344458) in children with growth hormone deficiency | Children who completed a prior TransCon hGH pediatric trial continued once-weekly lonapegsomatropin across 63 sites in 15 countries, with height and safety followed for up to about six years. | Sustained catch-up growth was observed, with mean height standard deviation score approaching the average-stature range (about -0.39 at year 4) and no new safety signals; a minority of patients developed non-neutralizing anti-drug antibodies without effect on efficacy or safety. | Source |
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Safety & Cautions
- Lonapegsomatropin is a prescription growth hormone product that must be prescribed and monitored by a qualified clinician (typically an endocrinologist); this page is background information, not medical advice or a dosing recommendation.
- Growth hormone therapy is contraindicated in acute critical illness (after open-heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure), in people with active malignancy, in children with closed epiphyses (for growth promotion), and in certain other conditions such as active proliferative diabetic retinopathy and Prader-Willi syndrome with severe obesity or respiratory impairment.
- Class effects of growth hormone include fluid retention and edema, joint and muscle pain (arthralgia and myalgia), carpal tunnel syndrome, headache, reduced insulin sensitivity and higher blood glucose, and suppression of thyroid or cortisol axes that may unmask hypothyroidism or adrenal insufficiency; benign intracranial hypertension and slipped capital femoral epiphysis have been reported in children.
- Growth hormone can increase the risk of growth or recurrence of tumors, particularly in patients previously treated with radiation to the head or brain for childhood cancer; patients with a history of malignancy require careful evaluation and monitoring.
- Anti-drug antibodies were detected in a minority of pediatric patients in clinical trials with no clear effect on efficacy or safety and no neutralizing antibodies identified, but immunogenicity is monitored as with any biologic.
- Any product sold online as 'lonapegsomatropin,' 'TransCon hGH,' or 'Skytrofa' outside a licensed pharmacy is unverified and potentially counterfeit or unsafe; genuine growth hormone therapy is dispensed only by prescription.
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Citations
- [1] FDA Approves SKYTROFA (Lonapegsomatropin-tcgd) for the Once-Weekly Treatment of Adults with Growth Hormone Deficiency - Ascendis Pharma (July 2025) PubMed
- [2] FDA Approves Skytrofa (lonapegsomatropin-tcgd) for the Once-Weekly Treatment of Adults with Growth Hormone Deficiency - Drugs.com (2025) PubMed
- [3] SKYTROFA (lonapegsomatropin-tcgd) for injection - Full Prescribing Information (DailyMed) PubMed
- [4] A Phase 3 Trial of TransCon hGH Weekly Versus Daily hGH in Children With Growth Hormone Deficiency (heiGHt; NCT02781727) - ClinicalTrials.gov PubMed
- [5] Children with Growth Hormone Deficiency Treated with Lonapegsomatropin Demonstrated Sustained Height Improvements for up to 6 Years: enliGHten Trial Final Results - Hormone Research in Paediatrics (Karger) PubMed
- [6] New InsiGHTS Trial of TransCon hGH (Lonapegsomatropin) in Turner Syndrome Achieved Primary Objective at Week 26 - Ascendis Pharma PubMed
- [7] Lonapegsomatropin Proves Long-Term Benefit for Adult GHD in Phase 3 foresiGHt Extension Trial - HCPLive PubMed
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