Somatrogon

A once-weekly recombinant growth hormone fusion protein, the full hGH sequence flanked by three copies of the hCG beta-subunit C-terminal peptide, FDA approved as Ngenla for pediatric growth hormone deficiency; the adult program missed its primary endpoint.

Also referenced as: Somatrogon-ghla, Ngenla, MOD-4023, hGH-CTP

Also appears in: Hormone

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What is Somatrogon?

Somatrogon is a long-acting growth hormone fusion protein, not a short peptide: a single 275-amino-acid chain expressed in Chinese hamster ovary cells in which the complete 191-residue human growth hormone sequence is flanked by three copies of the 28-residue C-terminal peptide (CTP) of the human chorionic gonadotropin beta-subunit, one at the N-terminus and two in tandem at the C-terminus. The CTP segments are O-glycosylated on 12 to 18 serine residues, which brings the molecular weight to roughly 40 kDa (against about 22 kDa for hGH itself) and is what extends the circulating half-life from hours to days. The same borrowing from hCG was first used to make a long-acting follitropin and was later applied to somatropin by the same group, which carried it through development as MOD-4023 and hGH-CTP.

Developed by OPKO Health and partnered with Pfizer since 2014, somatrogon is marketed as Ngenla (US nonproprietary name somatrogon-ghla) for pediatric growth hormone deficiency. It is the third once-weekly growth hormone approved in the United States, after somapacitan and lonapegsomatropin, and it is a prescription biologic with no research-market presence.

How it works

Somatrogon is a growth hormone receptor agonist; the fusion changes how long the molecule stays in circulation, not what it does once bound.

• CTP tail. The hCG beta-subunit C-terminal peptide is a serine-rich, O-glycosylated extension that accounts for hCG’s much longer half-life than luteinizing hormone and adds no hormonal activity; fusing it to the follitropin beta-subunit produced a long-acting FSH agonist, establishing the CTP as a transferable half-life module (Fares et al., Proceedings of the National Academy of Sciences, 1992, 89(10):4304–4308).
• Three CTP copies. Chimeric genes fusing hGH to one, two or three CTP cassettes were compared in hypophysectomized rats; the CTP–hGH–CTP–CTP arrangement injected once every 5 days produced weight gain matching daily recombinant hGH at the same total dose, with higher cumulative IGF-1 and markedly increased half-life, mean residence time and area under the curve, and this construct became MOD-4023 (Fares et al., Endocrinology, 2010, 151(9):4410–4417).
• Affinity versus residence time. In vitro, MOD-4023 bound the GH receptor with lower affinity and reduced potency than recombinant hGH, yet in rats and rhesus monkeys its serum half-life was significantly longer, exposure matched daily hGH, IGF-1 rose with repeated dosing, and twice-weekly injections produced more weight gain than daily hGH at a lower cumulative dose, consistent with the extended half-life increasing the total number of receptor interactions (Hershkovitz et al., Molecular Pharmaceutics, 2016, 13(2):631–639).
• Pharmacokinetics. In the approved label’s population analysis, somatrogon reaches peak concentration a median 11 hours (range 6 to 25 hours) after subcutaneous injection, has an effective half-life of about 37.7 hours, and remains in circulation for about 8 days after a dose; in the pediatric dose-finding study its estimated half-life was about five- to tenfold longer than daily recombinant hGH, with dose-dependent IGF-1 responses (Zelinska et al., Journal of Clinical Endocrinology & Metabolism, 2017, 102(5):1578–1587).

Research status

Somatrogon has a completed registrational program in children, a failed placebo-controlled program in adults, and long-term extension data reaching nine years in a small cohort. Every pediatric efficacy trial was an open-label comparison with daily somatropin; the only placebo-controlled trial was the adult study.

Pediatric Phase 2 and its extension (NCT01592500). An open-label, randomized dose-finding study at 14 European centers compared three weekly MOD-4023 doses with daily recombinant hGH in prepubertal children with GHD; 53 children completed 12 months (42 on MOD-4023, 11 on daily hGH), all MOD-4023 groups showed catch-up growth, and the highest dose most closely matched daily hGH, with no serious adverse events (Zelinska et al., Journal of Clinical Endocrinology & Metabolism, 2017, 102(5):1578–1587). Forty-eight children entered an open-label extension. At 5 years, height SDS and change in height SDS were sustained (Zadik et al., Journal of Pediatric Endocrinology and Metabolism, 2023, 36(3):261–269); at up to 9 years, mean annualized height velocity stayed above 5 cm/year, height SDS improved from −4.0 at baseline to −0.2 by year 8, treatment-emergent adverse events fell from 52.1% in extension year 1 to 23.8% in year 9, and anti-drug antibodies were present without neutralizing activity or any detectable effect on growth (Mauras et al., Journal of Clinical Endocrinology & Metabolism, 2026, online ahead of print, June 2026).

Pediatric Phase 3 pivotal trial (NCT02968004). A 12-month, open-label, randomized, active-controlled study at 83 sites in 21 countries randomized 228 treatment-naive prepubertal children (boys 3–11, girls 3–10) 1:1 to once-weekly somatrogon or once-daily somatropin; 224 received at least one dose (109 somatrogon, 115 somatropin). Annualized height velocity at month 12 was 10.10 versus 9.78 cm/year, a treatment difference of 0.33 cm/year (95% CI −0.24 to 0.89), whose lower bound cleared the prespecified noninferiority margin of −1.8 cm/year. Treatment-emergent adverse events were similar (78.9% versus 79.1%) and mostly mild to moderate (Deal et al., Journal of Clinical Endocrinology & Metabolism, 2022, 107(7):e2717–e2728). The label reports injection-site reactions in 42.2% of somatrogon-treated children versus 25.2% on daily somatropin. In the open-label extension, 212 children continued or switched to somatrogon; mean height velocity was 8.11, 7.91, 7.02 and 6.56 cm/year in extension years 1 through 4, height SDS approached 0 by year 4, switched patients grew like continuously treated ones, and up to a quarter of patients had IGF-1 SDS above 2 at two consecutive visits in the first two extension years, meeting protocol criteria for dose reduction (Stawerska et al., Hormone Research in Paediatrics, 2026, online ahead of print, June 2026; Stawerska et al., Journal of the Endocrine Society, 2026, 10(11):bvag175). The study was formally completed in May 2024; near-adult-height data have not been reported.

Japanese Phase 3 (NCT03874013). Forty-four prepubertal Japanese children were randomized 1:1 to weekly somatrogon or daily somatropin for 12 months. Least-squares mean height velocity was 9.65 versus 7.87 cm/year (difference +1.79 cm/year; 95% CI 0.97 to 2.61), meeting noninferiority against the same −1.8 cm/year margin; a similar proportion in each group reported injection-site pain, but the somatrogon group reported more painful injections (Horikawa et al., Hormone Research in Paediatrics, 2022, 95(3):275–285).

Treatment-burden crossover study. A Phase 3, randomized, open-label, two-period crossover at 20 centers in five countries enrolled 87 children aged 3 to under 18 already on stable daily hGH; using a patient–caregiver dyad questionnaire, mean life-interference scores were 8.63 after the weekly period versus 24.13 after the daily period (difference −15.49; 95% CI −19.71 to −11.27), while adverse events were somewhat more frequent on somatrogon (54.0% versus 44.2%). The study measured perceived burden, not growth (Maniatis et al., Journal of the Endocrine Society, 2022, 6(10):bvac117).

Adult GHD Phase 3 (NCT01909479). After a Phase 2 dose-finding study in 54 adults switched from daily GH, which showed dose-dependent pharmacokinetics and IGF-1 responses and closed its lowest-dose cohort for poor efficacy (Strasburger et al., European Journal of Endocrinology, 2017, 176(3):283–294), OPKO ran a randomized, double-blind, placebo-controlled Phase 3 with a 26-week blinded period followed by open-label extensions. Of 389 screened, 202 adults were randomized 2:1 and 198 treated (133 somatrogon, 65 placebo). Topline results announced in December 2016 missed the primary endpoint, and the full publication confirms it: change in trunk fat mass from baseline to week 26 was −0.37 kg on somatrogon versus +0.03 kg on placebo (P = 0.0821), with no significant difference in total fat mass either; lean body mass and several secondary or post hoc body-composition measures did improve, and IGF-1 SDS normalized (Fleseriu et al., Pituitary, 2026, 29(2):59). The sponsor’s June 2017 post hoc analyses excluding outliers were never accepted as a basis for approval. ClinicalTrials.gov lists the study as terminated because the long-term open-label extension was stopped once the main study had completed. In Europe, Pfizer applied to extend Ngenla’s indication to adults and withdrew the application on December 20, 2024; the EMA’s published position was that, on the data submitted, the adult indication could not have been authorized because neither the primary nor the other efficacy measures showed benefit over placebo. No US application for an adult indication is on record, and Ngenla remains a pediatric-only product in every market.

Regulatory record. The US BLA (761184) was received on October 22, 2020; a major amendment on September 15, 2021 extended the review goal date by three months, and the review ended in a complete response letter dated January 21, 2022, for which no reason was publicly disclosed. Pfizer resubmitted on November 22, 2022 and the FDA approved Ngenla on June 27, 2023 for pediatric patients aged 3 years and older with growth failure due to inadequate secretion of endogenous growth hormone. Health Canada approved it in October 2021, Australia’s TGA in November 2021, Japan’s MHLW in January 2022, and the European Commission on February 14, 2022 for patients from 3 years of age. Labeling supplements followed, most recently a prescribing-information update approved on April 29, 2026 adding epiphysiolysis and lipoatrophy information, with the current label revised in August 2026; the indication has not changed.

Post-approval evidence. A propensity-matched comparison of trial growth outcomes against daily-GH registry data (Deal et al., Journal of the Endocrine Society, 2026, 10(9):bvag186), a real-world matched-cohort study (Orman et al., Annals of Pediatric Endocrinology & Metabolism, 2026, online ahead of print), a European transition series in isolated GHD (Sotiriou et al., European Journal of Endocrinology, 2026, 195(4):590–599) and a Japanese single-arm study of children switched from somatrogon to somapacitan because of injection-site pain (Iwayama et al., Frontiers in Endocrinology, 2026, 17:1849487) have appeared in 2026, broadly reproducing the trial efficacy while keeping injection-site tolerability in focus.

Common dosage forms

• Prefilled multidose pens. Single-patient-use pens contain 24 mg in 1.2 mL (20 mg/mL) or 60 mg in 1.2 mL (50 mg/mL) as a clear, colorless to slightly yellow solution that needs no reconstitution. Japan and the EU use the same 24 mg and 60 mg pens.
• No vial or powder presentation. No bulk, vial or powder presentation exists in any market.

Key considerations

• Regulatory status. The FDA Approved status reflects Ngenla (BLA 761184), approved June 27, 2023 for growth hormone deficiency in children aged 3 and older. No adult indication exists anywhere. The label carries the somatropin-class contraindications and warnings.
• Fusion protein, not peptide. Somatrogon carries no hCG hormonal activity: the CTP segments are glycosylated spacers that slow clearance, not receptor-binding domains. It shares the GH receptor with somatropin but with lower intrinsic affinity, a weekly IGF-1 profile and a different dosing unit, so milligram or IU comparisons with daily GH are not meaningful. It is distinct from albumin-binding somapacitan, from the PEGylated prodrug lonapegsomatropin and from the unrelated fragment “HGH 176-191”.
• Surrogate endpoints. The pivotal and Japanese trials compared 12-month height velocity against daily somatropin in open-label, noninferiority designs; neither was placebo-controlled nor powered on adult height. Near-adult-height data, fracture and cardiometabolic outcomes, and safety beyond a decade are not yet available for any long-acting GH.
• Immunogenicity and injection-site reactions. In the pivotal period 77.1% of somatrogon-treated children developed anti-drug antibodies and 3.7% developed transient neutralizing antibodies over up to 42 months, with no detected effect on growth or safety. Injection-site reactions were substantially more common than with daily somatropin, injection-site pain was the most frequent treatment-related event in every extension, and hypothyroidism was also reported more often (6.4% versus 2.6%).
• Naming. MOD-4023, hGH-CTP, somatrogon, somatrogon-ghla and Ngenla are one molecule at different stages; “-ghla” is a nonproprietary-name suffix, not a different product. “CTP” here means the hCG C-terminal peptide, not a dosing or chemical abbreviation.